Antibody–drug conjugates (ADCs) are a potential and promising therapy for a wide variety of cancers, including breast cancer. ADC-based drugs represent a rapidly growing field of breast cancer therapy. Various ADC drug therapies have progressed over the past decade and have generated diverse opportunities for designing of state-of-the-art ADCs. Clinical progress with ADCs for the targeted therapy of breast cancer have shown promise. Off-target toxicities and drug resistance to ADC-based therapy have hampered effective therapy development due to the intracellular mechanism of action and limited antigen expression on breast tumors. However, innovative non-internalizing ADCs targeting the tumor microenvironment (TME) component and extracellular payload delivery mechanisms have led to reduced drug resistance and enhanced ADC effectiveness. Novel ADC drugs may deliver potent cytotoxic agents to breast tumor cells with reduced off-target effects, which may overcome difficulties related to delivery efficiency and enhance the therapeutic efficacy of cytotoxic cancer drugs for breast cancer therapy. This review discusses the development of ADC-based targeted breast cancer therapy and the clinical translation of ADC drugs for breast cancer treatment. ADC-based drugs span the gap between mAb and cytotoxic drugs used to enhance the therapeutic effectiveness of cancer therapy, including breast cancer. The four key components of an ADC are the targeting antigen, the monoclonal antibody (mAb), the payload, and the linker. ADCs consist of an anticancer mAb conjugated to a cytotoxic payload through an engineered chemical linker that enables the effective targeting of tumor cells and a killing effect simultaneously . ADCs haThe vital step of ADC development is the selection of target antigens . Once thCurrently, more than 12 ADCs have received Food and Drug Administration (FDA) approval for hematological malignancies and solid tumors, and around 100 ADC drugs are currently in different phases of clinical trials . Most ofIn 2020, sacituzumab govitecan received accelerated approval for metastatic TNBC (triple-negative breast cancer) patients who have received at least two prior therapies for metastatic disease. In 2021, the FDA finally approved sacituzumab govitecan  for patients with unresectable, locally progressed or metastatic TNBC who had experienced two or more prior systemic treatments, with at least one of them for metastatic disease. In 2022, another ADC drug, fam-trastuzumab deruxtecan-nxki (Enhertu), received FDA approval for unresectable or metastatic HER2-low breast cancer patients who had received prior chemotherapy for a metastatic disease or had developed disease relapse during or within six months of finishing adjuvant therapy. Around 40 to 50% of breast cancer patients have tumors with low HER2 expression. HER2-low breast cancer is defined as immunohistochemistry [IHC]1+ or IHC2+ with no HER2-amplification  . In FebrSacituzumab govitecan is composed of an antibody coupled to topoisomerase I inhibitor (SN-38) through a proprietary hydrolysable linker, and it targets human trophoblast cell-surface antigen 2 (TROP-2), which is overexpressed in many epithelial cancers, including a majority of breast cancers . An overADC-based drugs signify a growing field of cancer therapy, including for breast cancer. Different ADC drug technologies advanced over the past decade have generated a variety of opportunities for engineered innovative ADCs . AdvanceFurthermore, the combination approaches that utilize ADCs in clinical trials are being explored extensively, for example by combining them with immune checkpoint inhibitors (ICIs) and chemotherapeutics.Thus, the development of new ADC drugs has offered huge opportunities for the treatment of cancer, including breast tumors . The expCurrently, ADC drugs require internalization to release the cytotoxic payload, which generates a hurdle for therapeutic development in that it requires cancer cell targets that overexpress internalizing antigens for effective intracellular processing .However, an alternative strategy is emerging for the extracellular release of the payload from cleavable linkers: its binding to weakly internalizing antigens or other constituents of a tumor, such as secreted proteins in the tumor microenvironment (TME). This may eliminate the dependence on the overexpression of antigen, avoid inefficient internalization, and potentially improve the variety of cancer targets in the components of the extracellular tumor matrix for an enhanced therapeutic effect .In addition to the well-recognized ADC targets, including HER2, EGFR, FGFR and c-MET, there are many emerging ADC target antigens, including TROP-2, CD-25, EpCAM, demonstrating promising outcomes in solid tumor therapy in preclinical and clinical settings  8,37]. ,37. 8,37The majority of the current ADC drugs utilize the internalizing mechanism. After the ADCs’ binding to the target antigen expressed on the cancer cell, the ADCs are internalized through endocytosis and subsequently degraded in the lysosome, and the cytotoxic payload is released A 8]. Th. Th8]. TNon-internalizing ADCs may utilize an alternative mechanism of action. In non-internalizing ADCs, instead of necessitating lysosomal disintegration to release payload intracellularly, the ADC’s labile linkage may provide the release of the payload into the extracellular TME, targeting the distinct chemical/enzymatic atmosphere of the tumor, and they may disperse into neighboring cancer cells to exert their cytotoxic effect B. Non-inInternalizing ADCs usually utilize non-cleavable linkers, which involve the mAb degradation of their integral amino acids for the release of a cytotoxic payload into the lysosome. The charged nature of attached amino acids render it incapable of dispersing across the cell membrane and inhibit nearby cancer cells through a bystander effect. ADCs that use non-cleavable linkers necessitate effective cellular trafficking. Non-cleavable linkers are effective for internalizing ADCs. Among the currently approved ADCs for breast cancer therapy, only trastuzumab emtansine possesses a non-cleavable linker . CleavabInternalization is key to the effectiveness of ADCs with cleavable linkers. However, increasingly, several indications suggest a contrary mechanism. The dying tumors may release the intracellular linker triggers into the extracellular TME, facilitating the non-internalizing mechanisms of ADC. These linkers may be incorporated into non-internalizing ADCs. Therefore, the concept that the linker must persist in circulation before internalization and detachment within the cancer cells may need to be modified for non-internalizing ADCs. The linkers comprising ester or carbonate groups with modest stability in circulation have been utilized in integration with antibodies targeting the stromal constituents in the TME, permitting a persistent local drug release into tumors. Carbonate linkers already have been proven in a clinical setup (Sacituzumab govitecan). This linker type may be utilized only with moderately cytotoxic payloads. However, off-target toxicity due to labile linkages should be investigated .ADCs’ effectiveness depends on several features of target antigens ,5. For iBreast cancer is the most frequently diagnosed cancer in women, which is the second most prevalent cause of death among cancers. In 2020, 11.7% of newly diagnosed cancer cases were for breast cancer, which significantly endangered women’s health worldwide and was the main cause of female death .Currently utilized therapies for breast cancer are chemotherapy, radiation therapy and surgical resection. These options are associated with severe side effects, therapy resistance and disease recurrence. In metastatic disease, therapy options are more limited, and a majority of patients will die from the disease. In recent years, targeted therapy using ADCs have greatly advanced the treatment of breast cancer by utilizing HER2-targeted, HR-targeted, and TNBC-targeted ADCs .HER2-targeted therapies of breast cancer have shown promising results in clinic. Some of the HER-2 targeted therapies have been approved by FDA , and some others are in late stages of clinical trials .Trastuzumab emtansine TDM-1) was approved for the treatment of patients with unresectable or metastatic HER2-positive breast cancer. The approval was based on the EMILIA trial for patients who received trastuzumab and taxane or reverted during the therapy or within 6 months following adjuvant therapy . DM1 is  was apprThe KATHERINE trial supported TDM1-1 as the standard adjuvant treatment for patients with HER2-positive breast cancer . The devT-DM1 remains a second-line standard therapy for HER2-positive breast cancer patients. According to the phase III MARIANNE trial, the TDM-1 with or without pertuzumab demonstrated no improvement in PFS as a first-line treatment for metastatic HER2-positive breast cancer . The CLETrastuzumab deruxtecan was approved based on the results of the DESTINY-Breast01 study. This approval is for breast cancer patients with HER2-positive unresectable or metastatic disease who received a minimum of two previous anti-HER2 therapies . HoweverUpon binding to HER2, T-Dxd is internalized and trafficked intracellularly to the lysosome . The linBoth the in vitro and in vivo pharmacological function of T-Dxd was evaluated and compared to T-DM1 using patient-derived xenograft (PDX) models . The higT-Dxd was investigated in several clinical trials for solid tumors focusing on breast cancer. In 2015, a phase I first-in-human trial included highly treated patients with progressed HER2-positive breast cancer . Breast T-Dxd received FDA approval in 2020 . In 2019The DESTINY-Breast02 study is a phase III, open level, randomizing one of two arms, T-Dxd versus treatment of physician choice (TPC) (a combination of capecitabine with either trastuzumab or lapatinib) trial for HER2-positive metastatic breast cancer patients previously treated with T-DM1. Fam-trastuzumab deruxtecan-nxki led to higher response rates and longer survival times in a third-line setting for HER2-positive metastatic patients pretreated with T-DM1. According to the result form the DESTINY-Breast02 phase III study presented at the 2022 San Antonio breast cancer symposium (Abstract GS2-01), among the 608 patients enrolled and treated with T-Dxd, 69.7% experienced an objective response compared to TPC (29.2%). Those patients treated with T-Dxd were 64% less likely to experience disease progression than the patients that received TPC. The PFS was 17.8 months for T-Dxd-treated patients versus 6.9 months (TPC). The OS was 39.2 months for the patients treated with T-Dxd versus 26.5 months with TPC .The outcomes of the DESTINY-Breast03 trial were presented in 2021 ,41. In tT-Dxd has been allied with higher rates of toxicities, including grade 5 events . The stuTrastuzumab duocarmazine (SYD985) is an anti-HER2 ADC composed of anti-HER2 mAb with the same sequence of trastuzumab, conjugated to a cleavable linker comprising duocarmycin. Duocarmycin results in DNA degradation in cancer cells, eventually resulting in cancer cell death . ProteasThe results of a first-in-human, phase I clinical trial of trastuzumab duocarmazine evaluated dose-escalation and expansion (NCT02277717) in 146 patients with HER2-positive locally progressed or metastatic solid tumors, refractory to standard cancer therapy . A prospThe phase III TULIP trials included the evaluation of the PFS of trastuzumab duocarmazine versus TPC (NCT03262935). The preliminary result of the TULIP study was reported at the 2021 ESMO meeting . In thisThe ADC drug disitamab vedotin (RC48-ADC) consists of an mAb (disitamab) that targets HER2 and a cleavable linker conjugated to the microtubule-disrupting, synthetic antineoplastic agent monomethyl auristatin E (MMAE). Investigations have demonstrated that RC48-ADC inhibits tumor cells, effectively targeting HER2 . SuperioThe US-FDA has approved Sacituzumab govitecan-hziy for the treatment of patients with unresectable locally progressed or metastatic hormone receptor positive (HR+) and HER2-negative breast cancer. This approval is for breast cancer patients who experienced endocrine treatment and a minimum of two more systemic therapies for metastatic disease. Sacituzumab govitecan is comprised of an antibody coupled to a topoisomerase I inhibitor through a hydrolysable linker. This is the first approved ADC drug targeting TROP-2 for the treatment of metastatic HR+ and HER2-negative breast tumors ,6,18. ThThe TROPiCS-02 trial demonstrated an OS benefit of 3.2 months from Sacituzumab govitecan-hziy compared to TPC  for patients with metastatic HR+ and HER2-negative breast tumors . In thisHER3 is upregulated in metastatic breast cancer and other cancers, and it has been associated with poor outcomes ,71. The ARX-788 is an innovative ADC consisting of anti-HER2 mAb, a noncleanable linker and a proprietary of MMAF (Amberstatin 269 or AS269). ARX-788 demonstrated more efficacy than T-DM1 for the inhibition of breast tumors resistant to T-DM1 . ARX-788The A166 ADC drug consists of an anti-HER2 antibody and an effective MMAF-based payload (duostatin-5) conjugated via a cleavable valine-citrulline linker . A phaseThe ADC drug MRG002 consists of an anti-HER2 IgG1 mAb, a microtubule- disrupting agent, and MMAE, and is conjugated through a valine–citrulline cleavable linker . This ADAnother innovative ADC drug, ALT-P7 (HM2-MMAE), is composed of trastuzumab biobetter HM2 conjugated to the payload MMAE . A phaseThe HER-directed ADC drug ADC GQ1001 is a novel ADC drug with a trastuzumab mAb and DM1 cytotoxic payload, currently undergoing phase I/II clinical trial (NCT04450732) for HER2-positive tumors . The SBTTNBC is allied with a poor prognosis and has limited therapy options due to the missing of targets such ER, PR and HER2. TROP-2 is a calcium signal transducer found in a majority of epithelial carcinomas. It is overexpressed in breast cancer and TNBC tumors. TROP-2 is expressed in healthy tissues as well, with low expression. The ADC drug Sacituzumab govitecan targeting TROP-2 in TNBC cells has received approval from the FDA for TNBC therapy . SacituzSacituzumab govitecan received accelerated FDA approval for TNBC patients in 2020. In 2021, Sacituzumab govitecan received regular approval by FDA for patients with unresectable locally progressed or metastatic TNBC. This approval is for patients who experienced two or more prior systemic therapies, with a minimum of one of them for metastatic disease. Sacituzumab govitecan was first investigated by Bardia et al. in the IMMU-132-01 trial (NCT01631552), which was a phase I/II basket study that included 108 patients with advanced epithelial cancer who experienced a minimum of two previous therapies for metastatic TNBC . The outBRCA1/2 mutation status. Patients with a high or medium TROP-2 expression level got an advantage from Sacituzumab govitecan therapy versus TPC in terms of ORR, PFS and OS. Because of the low number of patients with low TROP-2 expression, a definitive conclusion was difficult to make. Another subgroup analysis of TNBC patients with brain metastasis in the ASCENT study (n = 61) demonstrated better efficacy for Sacituzumab govitecan compared to TPC . La. La90]. Preclinical studies demonstrated that ladrituzumab vedotin binds explicitly to the extracellular domain of LIV-1. After internalization, ladrituzumab vedotin releases its payload by proteolysis in the lysosome and results in the inhibition of microtubulin and prompts apoptosis .A phase I study evaluated the safety, acceptability, pharmacokinetics, and tumor inhibition activity of ladrituzumab vedotin in patients with LIV-1-positive, unresectable, locally progressed or metastatic breast cancer who had a minimum of two or more cytotoxic treatments; ladrituzumab vedotin was administered every 3 weeks (NCT01969643) . The outIn an I-SPY study (NCT0102379) ladrituzumab vedotin was evaluated in patients with stage II/III breast cancer with neoadjuvant therapy with pCR as a major endpoint compared paclitaxel weekly for 12 weeks . This stAs of February 2023, a total of twelve ADCs have received approval for different cancers, including three for breast cancer and TNBC therapy. Currently, more than 100 ADCs are in different phases of clinical trial. Among them, at least 13 are being evaluated for breast cancer therapy. ADCs targeting either HER or TNBC are potential therapeutics for breast cancer patients. The development of ADCs in the last decade has revolutionized breast cancer therapy ,102. CurADCs, either targeting human epidermal growth factor receptor or TROP-2, are prospective treatment approaches for breast cancer patients. The growth of ADC-based drugs in the last decade has greatly enhanced breast cancer therapy. Three HER2-targeted ADCs have received approval for HER2-positive metastatic breast cancer patients, and one ADC drug was approved by the FDA for TNBC therapy. There are also many promising ADC drugs for breast cancer patients undergoing different phases of clinical trials. Ways to enhance the cancer cell uptake of ADCs have been key and have been allied with ADC development because most of the current ADCs depend on the expression of target antigens on tumor cells. An optimal patient selection approach necessitates the consideration of the intratumoral heterogeneity of the target antigen and dynamic changes in antigens associated with treatment and disease stages and optimizing the threshold of target antigen expression to improve ADC therapy in the clinical setting. Systemic toxicity is one of the major factors for the failure of ADCs in the clinical setup. Following ADC administration, the released payload rapidly appears within systemic circulation, which may cause systemic toxicity. Plasma exposure to released payload relates, partly, to the early deconjugation of the payload in circulation due to insufficient linker stability. Cleavable ADC linkers are frequently hydrolyzed at significant rates, leading to the premature release of the cytotoxic payload in the extra-tumoral compartments. Lipophilic payloads demonstrate high permeability through plasma membranes. Consequently, the free payload enters non-targeted cells via membrane diffusion, resulting in unwanted cytotoxicity. Approximately 0.1% of the administered ADC drugs are delivered to targeted tumor cell populations, with the vast majority of the injected dose catabolized ‘off-site’ within non-targeted healthy cells, leading to a potential unwanted toxicity. Off-site ADC toxicity may be of two types: on-target and off-target. On-target toxicity is due to the ADC binding to targeted cell surface protein of healthy cells, and off-target toxicity is due to non-targeted ADC binding .The increasing attrition rate of ADCs with antimitotic payloads is due to suboptimal efficacy at the maximum tolerated doses (MTDs) during clinical trial. Recent development of ADCs demonstrated the utilization of more potent DNA-damaging payloads. Highly potent ADCs often lead to high efficacy; however, their efficacy is hindered by their life-threatening toxicities. Therefore, the unwanted toxicity limits the clinical benefit of ADCs by restricting the tolerable doses to amounts below the levels required to provide optimal anticancer effect. Studies have demonstrated that for many ADCs, the exposures at the clinical MTDs were much lower than the exposures essential for efficacy in preclinical models. The approaches to extend the therapeutic windows of ADCs through the attenuation of ADC toxicities might permit enhanced MTDs and, afterward, better clinical results .Hepatotoxicity is included in one of the black box warnings for T-DM1 treatment, presenting as asymptomatic transient increases in serum transaminase. Black box warnings were added to the Sacituzumab govitecan label for severe or life-threatening neutropenia and severe diarrhea. Further, ILD and pneumonitis are included in the black box warning for patients treated with T-Dxd . Toxic e


Atypical anti-glomerular basement membrane (anti-GBM) disease is characterized by linear immunoglobulin G (IgG) deposition along the GBM without circulating IgG anti-GBM antibodies. Compared to classic anti-GBM disease, atypical anti-GBM disease tends to be milder with a more indolent course in certain cases. Moreover, pathologic disease pattern is much more heterogenous in atypical anti-GBM disease than in the classic type, which is uniformly characterized by diffuse crescentic and necrotizing glomerulonephritis. Although there is no single well-established target antigen in atypical anti-GBM disease, the target antigen (within the GBM) and the autoantibody type are hypothesized to be different from the classic type. Some patients have the same antigen as the Goodpasture antigen that are detected only by a highly sensitive technique . Some cases of atypical anti-GBM disease have autoantibodies of a different subclass restriction like IgG4, or of monoclonal nature. Antibodies targeting antigen/epitope structure other than the Goodpasture antigen can be detected using modified assays in some cases. Patients with IgA- and IgM-mediated anti-GBM disease are known to have negative circulating antibodies because conventional assays do not detect these classes of antibodies. A significant proportion of cases with atypical anti-GBM disease do not have any identifiable antibodies despite extensive evaluation. Nevertheless, extensive evaluation of atypical autoantibodies using modified assays and sensitive techniques should be attempted, if feasible. This review summarizes the recent literature on atypical anti-GBM disease. Anti-GBM disease is rare with an incidence of about 1 per million population per year.,Atypical anti-GBM disease comprises 8% to 12% of all anti-GBM disease cases.The antigen in classic anti-GBM disease, also called Goodpasture antigen, comprises cryptic epitopes of the noncollagenous 1 (NC1) domain of the α3 subunit of type IV collagen.,et al.Several methods for testing circulating anti-GBM antibodies include indirect immunofluorescence assay, enzyme-linked immunosorbent assay (ELISA), chemiluminescence, radioimmunoassay, multiplex bead test, western blot, and biosensor system. The sensitivity and specificity of commercial immunoassays, which measure the Goodpasture antigen, are 95% to 100% and 91% to 100%, respectively.Conformational epitopes on the alpha3NC1 domain of type IV collagen, other than Ea and Eb, were detected using nonreducing western blot analysis in anti-GBM disease patients with negative serology on ELISA.,,,,Serum anti-GBM antibodies are shown to correlate with clinical and pathologic severity of anti-GBM disease.Nonspecific polyclonal antibodies in the plasma could alter the detection of anti-GBM antibodies.et al.et al.et al.,,,,Deposition of autoantibodies along the GBM leads to complement activation and inflammation followed by rupture of the GBM and fibrinoid necrosis in the endocapillary tuft. Leakage of proinflammatory plasma into the Bowman’s space causes parietal epithelial cell activation and crescent formation, typically diffuse involving >50% of the glomeruli.,,,,,,,,,,,Classic anti-GBM disease presents abruptly with severe kidney with or without lung involvement. Nephritic syndrome and rapidly progressive glomerulonephritis are typical clinical manifestations of classic anti-GBM disease, characterized by a rapid clinical deterioration of the glomerular filtration rate. Patients present with rapid onset of oliguria or anuria followed by volume overload, often with hemoptysis. Atypical anti-GBM disease is a milder disease with an indolent course. Although kidney dysfunction was common (53%–75%), the median serum creatinine at presentation was mildly elevated (1.61–1.9 mg/dl),,,,Treatment of atypical anti-GBM disease has been heterogenous, including nonimmunosuppressive conservative therapies like renin-angiotensin-aldosterone blockers monotherapy (43.3%), immunosuppressive therapy like steroids, cyclophosphamide, mycophenolate mofetil, tacrolimus, rituximab (50%–70%), and rarely plasmapheresis (6.7%–10%).et al.,Although IgA-mediated anti-GBM disease is not a variant of atypical anti-GBM disease (because the deposited Ig in the GBM is IgA and not IgG), false-negative serology on conventional assays could initially mimic atypical anti-GBM disease. IgA-mediated anti-GBM disease is rare, with only 16 case reports in the literature to date,,et al.et al.IgG4-mediated anti-GBM disease is typically associated with favorable kidney outcomes.et al.,et al.et al.,Monotypic Ig deposits along the GBM, defined based on light chain restriction on IF of kidney tissue, are increasingly observed to cause a disease pattern similar to atypical anti-GBM disease. Patients typically lack circulating anti-GBM antibodies and have a milder presentation. In the study by Nasr ,Patients with diabetic nephropathy, monoclonal immunoglobulin deposition disease (MIDD), and fibrillary GN can have linear IgG deposition along the GBM . A passiAtypical anti-GBM disease is a variant of the classic anti-GBM disease characterized by linear Ig deposition along the GBM on kidney biopsy and lack of circulating antibodies. Other causes of linear Ig deposition along the GBM must be excluded based on concomitant pathology and clinical background. Kidney dysfunction is usually milder and evolves slower than classic anti-GBM disease; however, presentation as rapidly progressive glomerulonephritis has also been reported. Proteinuria and nephrotic syndrome are more frequent than classic anti-GBM disease. Light microscopy shows heterogenous patterns like mesangial and/or endocapillary proliferative GN, membranoproliferative glomerulonephritis, FSGS, mesangial sclerosis; and glomerular endothelial changes resembling thrombotic microangiopathy are common in atypical anti-GBM disease. Diffuse crescentic and necrotizing GN is uncommon. Differences in the entire target antigen or epitope structure and/or type of antibody can result in negative serology on commercial assays. Modified assays to detect a wide range of antigens or epitopes or antibodies and more sensitive techniques like biosensors can unmask circulating anti-GBM antibodies in some cases and should be attempted. The monotypic subtype of atypical anti-GBM disease needs further study to confirm if it is a form of monoclonal gammopathy of renal significance. Treatment of atypical anti-GBM disease is individualized and typically consists of immunosuppressive agents used to treat classic anti-GBM disease or monotherapy with renin-angiotensin-aldosterone blockers. A prospective multicenter study on a large cohort of patients with atypical anti-GBM disease would be worthwhile to understand its pathogenesis, clinical course, and outcomeUpToDate.com; reports serving on the editorial boards of CJASN, AJKD, CKJ, Journal of Onconephrology, Kidney International, and NDT; reports serving as Editor-in-Chief of ASN Kidney News and section editor for onconephrology for Nephrology Dialysis Transplantation. Other authors have nothing to disclose.KDJ reports consultancy agreements with Secretome, George Clinicals, PMV pharmaceuticals, and Calliditas. KDJ is a founder and co-president of the American Society of Onco-Nephrology (ASON); KDJ reports honoraria from the American Society of Nephrology, and


Anti N-methyl-d-aspartate receptor (anti-NMDA-R) encephalitis is a potentially reversible cause of psychosis. Nearly all patients (>95.5%) quickly develop additional neurological symptoms, and only about 50 percent fully recover, often with latency. At symptom onset, patients commonly present with isolated psychosis, making it challenging to distinguish the disease from a primary psychiatric disorder: The median time from symptom onset to immunotherapy in adults is 28 days (IQR 14–49), and from symptom onset to surgery in tumor-associated cases 1.4 months (IQR 0.7–2.6). Steroids, intravenous immunoglobulins (IVIG), or plasmapheresis are recommended as first-line immunotherapies.To highlight a case with improved outcome after very early combined first-line immunotherapy (steroids plus IVIG) and surgery in tumor-associated anti-NMDA-R encephalitis.Workup of the clinical case followed by a review of the literature.We present the case of a 33-year-old woman with sudden onset of anxiety and jealousy ideas, which within a few days, developed a manifest psychosis with formal thought disorders, paranoid and guilt delusions, distrust, and orientation disorders in the absence of additional neurological deficits. A lower abdominal tumor suspicious of an ovarian tumor was detected sonographically five days before the onset of the first symptoms. Lumbar puncture and abdominal computer tomography were performed within 30 hours after hospital admission, confirming the diagnosis of tumor-associated anti-NMDA-R encephalitis with autoantibodies in CSF and serum at a very early clinical stage. First-line immunotherapy with steroids  was started immediately and combined with IVIG therapy . Surgery of the ovarian tumor was performed on day 14 after admission, with histology revealing an immature teratoma. The neuropsychatric examination on day 1 after surgery showed complete remission of clinical symptoms, which persisted during clinical follow-up after 1 and 4 months.The present case highlights the role of early CSF diagnostic and tumor assessment if autoimmune encephalitis is suspected. Very early first-line immunotherapy with steroids and IVIG, complemented by tumor surgery, was associated with improved outcome in this case with anti-NMDA-R encephalitis. Further studies are warranted to evaluate the generalizability of the finding.None Declared


Crude samples were phytochemically analyzed via RP-HPLC revealing rutin, gallic acid, catechin, syringic acid, emodin, luteolin, myricetin, quercetin, and antifungal potential against dermatophytes, non-dermatophytes, Candida albicans, and yeasts was evaluated. Furthermore, the synergistic efficacy of amphotericin-B and terbinafine was checked against different fungi via time-kill kinetics and proteins estimation. Tested samples showed anti-radical and antifungal potential against both dermatophytes and non-dermatophytes. Synergistic effect was observed between extracts and standard antifungal drugs with a 4-8-fold decline in the MICs, revealing time and dose-dependent antifungal effect. The inhibition of fungal protein was more dominant in synergy-group compared to extracts-groups alone.An impressive number of research articles and review manuscripts were submitted to this Research Topic for consideration and a total of seven manuscripts were accepted for publication. Abdelgawad et al. reported the potential efficacy of olive leaves and their phytochemicals against SARS-CoV-2. Olive leaves contain phytoconstituents as oleuropein, apigenin-7-O-glucoside, verbascoside, hydroxytyrosol, and luteolin-7-O-glucoside and triterpenoids like ursolic acid, oleanolic acid, and maslinic acid which have known anti-viral efficacy. They are also reported to exhibit anti-inflammatory properties which strengthen their potential against SARS CoV-2 mediated coagulatory infections and associated co-morbidities.Medicinal plants are rich in metabolites that exhibit diverse antimicrobial potentials . AbdelgaLi et al. tested the efficacy of 126 coumarin derivatives as potential anti-viral agents against Hantaan virus (HTNV) and their mechanism. Among the tested compounds, N6 exhibited considerable anti-HTNV activity with high selectivity index (10.9) and a decline in the viral titer at 5, 10, and 20 μM. N6 administration during early infection stages inhibited viral replication in the host cells as indicated by the results from the HTNV-infected newborn mice. Molecular docking studies revealed that N6 interacted with high affinity to the amino acids’ active sites. Treatment with N6 was observed to be mediated via inhibition of p (Ser473)Akt and HTNV nucleocapsid proteins expression.Li et al. performed high-throughput screening of the natural products library against a tick-borne fatal viral infection called severe fever with thrombocytopenia syndrome virus (SFTCV). The study identified three compounds  with high efficacy against SFTV. Toosendanin was the most potent; it interfered with the viral replication at internalization stage. Toosendanin also reduced the in-vivo viral load inside the infected animals with considerable histopathological changes. Moreover, it was subjected to anti-viral studies against bunyavirus and SARS-CoV-2 infections and a broad anti-viral effect was observed, thus signifying further studies for its potential clinical use.Dahibhate et al. reported the anti-Pseudomonas aeruginosa potential of cyclic disulfide diastereomer isolated from Bruguiera gymnorhiza bioactive fraction (BG138). BG138 was phytochemically characterization by GC-MS, IR, 1H-NMR, and 13C-NMR revealing the presence of brugierol and isobrugierol. BG138 was tested against microbial virulence factors, biofilm formation, expression of QS-related genes and quorum sensing molecules. BG138 exhibited antibacterial (MIC of 32 μg/mL) and dose-dependent anti-biofilm activities with bacterial morphological changes and improved propidium iodide uptake by the bacterial cells. Furthermore, it inhibited bacterial virulence factors with reduced motility and swimming potential. The expression of anti-quorum sensing genes and cell damaging potential against the bacteria revealed it as a potential source of novel bioactive resistance modifying compounds.Djearamane et al. studied the efficacy of zinc oxide nanoparticles (ZnO-NPs) on bacterial cell walls and their morphological changes using FTIR and SEM techniques. ZnO-NPs cellular accumulation was assessed via dispersive X-ray. They exhibited concentration-dependent inhibition of bacterial growth. ZnO-NPs were more effective against Enterococcus faecalis than Serratia marcescens with percent growth inhibition of 63.50% and 51.27%, respectively. This was associated with bacterial morphological changes, loss of integrity and cell death. In another study, Abbas et al. evaluated the synergistic effect of a phenolic compound propyl gallate in combination with orbifloxacin against the KVCC1423-resistant Escherichia coli strain, resulting in reduction of the MIC of orbifloxacin in combination therapy with a 74% decline in MIC of both drugs, considerable inhibition of biofilm formation and bacterial motility. Thus, this combination was observed as a useful synergistic antimicrobial against resistant E. coli strains.Green nanotechnology is an emerging field of research to improve target drug delivery and bioavailability . DjearamIn conclusion, this Research Topic’s objective was to consider both research and review papers related to the potential drug discovery of antimicrobial agents from natural sources. This Research Topic offered a new venue for researchers to share their cutting-edge research findings in the field of natural products, novel antimicrobial agents and antibiotic resistance modulators.


Immunological mechanisms may contribute to the causation of mental illness. Autoimmunity is most convincingly shown for anti-NMDA-R encephalitis and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS); disorders that overlap clinically with schizophrenia and OCD. Altered inflammatory cytokine production, glial activation and auto-antibodies have also been associated with schizophrenia and OCD. In these disorders, however, the treatment results with anti-inflammatory or immunomodulating drugs have hitherto been limited and inconsistent. Yet other targets within the immune system may still be effective and new options are warranted for treatment-resistant patients. Rituximab targets B-lymphocytes and is often used in autoimmune disorders such as rheumatoid arthritis, multiple sclerosis and anti-NMDA-R encephalitis.We aimed to investigate whether rituximab is clinically effective, safe and tolerable as add-on therapy in markedly ill, treatment-resistant adult psychiatric patients with schizophrenia or OCD. We also wanted to identify putative mediating mechanisms in treatment responders, such as cytokine changes and functional connectivity (FC).In an open pilot study, adults (18-39 years) with treatment-resistant schizophrenia and/or OCD were included. They received an intravenous infusion of rituximab 1000 mg, once at baseline, in addition to their regular psychiatric medication and were followed for 1 year. The main outcome measures were the Positive and Negative Syndrome Scale (PANSS) or Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Clinical Global Impression-Improvement scale (CGI-I) and the Personal and Social Performance scale (PSP). Treatment response was defined as ≥ 40 % decrease in PANSS or ≥ 35 % decrease in Y-BOCS, and much improved according to CGI-I. Resting-state fMRI was applied at baseline and after 5 months. Plasma cytokines were measured at 0, 3 and 5 months. Cognitive tests and the recently developed PsychoNeuroinflammatory Related Signs and Symptoms Inventory (PNISSI) were used to identify and measure symptoms related to neuro-inflammation and cognitive function.Nineteen patients were treated with rituximab. 3-5 months after treatment, 6/9 patients with schizophrenia and 1/10 with OCD responded. One schizophrenia patient continues with rituximab every 6 months and has reportedly done well for almost 3 years. No severe side effects were reported apart from recurrent abdominal pain in a schizophrenia patient and one case of post-COVID-19 syndrome. Significant changes of FC were detected in responders only and correlated with PSP changes.Aberrant B-cell activities may contribute to treatment-resistant schizophrenia and be amenable to treatment with rituximab. However, the results of this pilot study need confirmation in placebo-controlled trials.None Declared


WOMAC scores also significantly decreased at 1 month (p < 0.001), but not at 6 months (p = 0.23). The ultrasound parameters did not significantly change, except color Doppler grading, which tended to decrease at the 6-month evaluation (p = 0.059). Our findings revealed that two ultrasound-guided HA injections following fluid drainage improved pain and knee function but did not considerably influence imaging-detected synovitis in patients with knee OA.We investigated whether hyaluronic acid (HA) injections can ameliorate ultrasound-detected synovitis in knee osteoarthritis (OA). We recruited 103 patients with symptomatic knee OA and ultrasound-detected synovitis and performed two ultrasound-guided fluid drainage procedures, followed by the administration of a low-molecular-weight HA injection (2.5 mL) in the subpatellar bursa, at a 2-week interval. Knee ultrasound imaging evaluations were performed before injection (baseline) and at 1 and 6 months after the second injection and included the measurements of synovial vascularity by using color Doppler ultrasound, synovial fluid depth over the suprapatellar bursa (SF), and synovial hypertrophy (SH). Initial clinical assessments included a visual analog scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). VAS scores decreased significantly at both 1-month and 6-month evaluations ( Osteoarthritis (OA) is a leading cause of disability in older adults and can affect all axial joints, including the spine, and appendicular peripheral joints. Knee OA causes a progressive decline in ambulation, considerably impairing activities of daily living . More thKnee OA involves all of the tissues of the knee joint and is characterized by cartilage and meniscal degeneration, subchondral bone remodeling, synovial membrane inflammation, infrapatellar fat pad inflammation, and fibrosis ,6. Low-gChronic conditions involving low-grade inflammation, such as diabetes and obesity, also contribute to and exacerbate the intra-articular inflammatory cascade in knee OA, due to insulin resistance and chronic hyperglycemia . These pN-acetyl-D-glucosamine. Its function depends on the rheological properties of molecular weights. HA is classified into high-molecular-weight (HWM) HA (molecular weight: >6.0 million Da) and low-molecular-weight (LMW) HA (molecular weight: 0.5–3.6 million Da) )  was used for all statistical analyses. The independent e [IQR]) . The WOMOrdinal data, such as color Doppler values, were analyzed using nonparametric Mann–Whitney U and Kruskal–Wallis tests. Spearman’s test and linear regression were used to determine the association between synovitis and the measured outcomes—specifically, whether changes in VAS and WOMAC scores were correlated with changes in ultrasound parameters.This study highlights the changes in ultrasound-detected synovial parameters after HA therapy for knee OA. Our data indicate that synovitis in knee OA, as measured using SF and SH, tends to persist and may be refractory to HA therapy despite clinical improvement and ultrasound-guided synovial fluid drainage before HA injection. Nevertheless, baseline SF and SH were correlated with VAS and WOMAC scores, suggesting that the severity of the synovial condition was closely related to symptoms. Moreover, low-grade vascularity was correlated with severity. Although the clinical efficacy of HA therapy was not improved by reducing synovial fluid or vascularity, our data provided a real-time synovial response to joint lavage with HA injection. Ultrasound-detected synovial parameters seem to be accurate for the real-time assessment of synovitis. Future studies should address different ultrasound-detected synovial responses to different therapeutic regimens in knee OA.


The use of metal nanoparticles (M-NPs) in cancer therapy has gained significant consideration owing to their exceptional physical and chemical features. However, due to the limitations, such as specificity and toxicity towards healthy cells, their application in clinical translations has been restricted. Hyaluronic acid (HA), a biocompatible and biodegradable polysaccharide, has been extensively used as a targeting moiety, due to its ability to selectively bind to the CD44 receptors overexpressed on cancer cells. The HA-modified M-NPs have demonstrated promising results in improving specificity and efficacy in cancer therapy. This review discusses the significance of nanotechnology, the state of cancers, and the functions of HA-modified M-NPs, and other substituents in cancer therapy applications. Additionally, the role of various types of selected noble and non-noble M-NPs used in cancer therapy are described, along with the mechanisms involved in cancer targeting. Additionally, the purpose of HA, its sources and production processes, as well as its chemical and biological properties are described. In-depth explanations are provided about the contemporary applications of HA-modified noble and non-noble M-NPs and other substituents in cancer therapy. Furthermore, potential obstacles in optimizing HA-modified M-NPs, in terms of clinical translations, are discussed, followed by a conclusion and future prospects. The rapid expansion of nanotechnology is attributed to multidisciplinary collaboration among researchers from academic, industrial, and federal sectors ,2. NanotAs the top cause of illness and mortality worldwide, cancer diseases are recognized as fatal malignancies. In 2020 alone, cancer resulted in approximately 9.9 million deaths and 19.2 million new cases worldwide. It is estimated that by 2040, the global cancer burden will rise to between 29–37 million new cases . The devDue to the drastic and unfavorable properties and substandard treatment results associated with conventional therapeutic methods, such as chemotherapy, radiotherapy, and surgery, there has been a significant shift in research towards the integration of nanotechnological approaches in cancer management ,9,10,11.To our knowledge, there are some reviews published individually on HA, M-NPs, HA and other NPs for cancer therapy and biomedical applications ,24,25,26The utilization of different types of M-NPs in cancer treatment has been widely explored. These M-NPs can be generally classified into two categories based on their chemical properties: noble and non-noble M-NPs. In the below section, a brief outline of noble M-NPs is provided.Au is recognized as a noble element because of its non-reactive characteristics, which enable it to withstand chemical oxidation, degradation, and corrosion, preserving its nature for prolonged periods, even for thousands of years. Au-NPs can be produced through different methods, including chemical, physical, biological, and green synthesis or even utilizing both bottom-up and top-down approaches. The exclusive physicochemical features of Au-NPs make them appropriate in cancer applications .The main modes of action by which Ag-NPs exert their effects include inducing oxidative stress, causing DNA rupture, and generating reactive oxygen species (ROS). ROS play a critical role in maintaining cellular homeostasis by regulating various signaling pathways. These highly reactive molecules are produced as byproducts of cellular metabolism. Nonetheless, when present in excess, intracellular ROS can trigger oxidative stress and induce impairment to cellular components, such as DNA, lipids, and proteins, thereby contributing to Ag-NP-induced toxicity . Ag-NPs Pt-based drugs, such as cisplatin, carboplatin, and oxaliplatin, are commonly used in cancer treatment for patients worldwide. Nevertheless, due to the drugs’ lack of specificity towards cancer cells, they can cause adverse reactions and contribute to the progress of drug resistance . CoatingResearchers have highlighted the exceptional catalytic and optical properties of Pd-NPs, making them suitable for theragnostic applications. Pd-NPs have been utilized as prodrug activators, and photothermal agents, as well as anticancer agents .Despite being prone to oxidation, non-noble metals offer several advantages, due to their low cost, abundance, localized therapy, enhanced side effects, and excellent conductivity. The following section describes the characteristic features of selected non-noble M-NPs used in cancer therapy.Manipulating magnetic NPs is made possible by the application of external magnetic fields . Owing tZn-NPs are among the most frequently occurring metallic NPs found globally, and their ability to generate ROS when exposed to light has recently gained significant attention. Chemical modification with biopolymers can enhance their photocatalytic effectiveness and ROS generation capacities .Due to the peculiar chemistry of cerium oxide, cerium oxide NPs (Ce-NPs) have been considered as potential anti-cancer agents . It has It is worth noting that M-NPs have been found to exhibit antitumor activity. The below paragraph outlines the typical mechanisms of action utilized in cancer treatments.The use of M-NPs in cancer therapy can improve the concentration of therapeutic agents through passive and active mechanisms. In particular, tumor vasculatures often display irregular branching and leaky areas, with pore sizes ranging from 100 nm to several hundred nanometers, attributed to the decreased presence of pericytes resulting from the swift proliferation of endothelial cells. This phenomenon is commonly observed in cancer treatments . The incHA can be derived from various sources, including microorganisms, cell-free systems, and animal tissues, as illustrated in The biosynthesis of HA originates with the phosphorylation of glucose by hexokinase to generate glucose-6-phosphate. This initiates two distinct pathways for the synthesis . The HA Cell-free systems represent an alternative approach for HA production; however, they remain suboptimal and unsuitable for large-scale industrial manufacturing. The Group A and C streptococci are known to possess Class I HAS enzymes that are characterized by their integral membrane structure containing 4–6 transmembrane domains and 1–2 membrane domains. These enzymes also possess the ability to be lipid-modified, which facilitates the extrusion of HA molecules outside the cell. Moreover, they can add UDP sugars from the reducing end of the HA chain to the developing HA polymer, making them a unique class of enzymes . VariousHA is a biopolymer comprised of D-glucuronic acid and N-acetyl-D-glucosamine units ,46. HA, 3 groups, that can be covalently modified. Among these, the carboxylic groups are particularly useful for chemical modification through amination or esterification or conjugation with M-NPs and other substituents [In more recent years, attention has been dedicated to natural polysaccharide polymers, owing to their various health promoting functions  ,55,56,57tituents ,59. The tituents . The CD4tituents .A multifunctional theranostic nanoplatform, comprised of laponite, polylactic acid, polyethylene glycol, polyethylenimine, Au and an HA system loaded with DOX drug (LAP-PLA-PEG-PEI--Au-HA/DOX), permits targeted chemotherapy and CT imaging of tumors. These hybrids have high loading efficiency of DOX at 91.0 ± 1.8% and pH-sensitive sustained release. In vitro experiments show that the designed hybrids can selectively deliver to CD44-overexpressing cancer cells, inhibit cancer cell proliferation, and enhance CT imaging. In vivo experiments demonstrate that hybrids can function as targeted contrast agents for CT imaging and effectively suppress tumor growth with reduced side effects . The ove2-HA-RGD) for dual-targeted chemo-photothermal therapy. The researchers tested the nanoplatform using DOX, a model drug, to evaluate its drug loading, in vitro drug release profiles, and effects on cells. They found that the nanoplatform demonstrated a favorable photothermal effect and could load drugs at a high capacity of around 20.16%. The additional experimental data examined cellular uptake studies which showed that the Au-NRs-mSiO2-HA-RGD nanoplatform could be targeted to ovarian cancer cells through dual mechanisms involving endocytosis mediated by CD44 and integrin receptors [In another work, Zhou et al. designed an integrated multifunctional nanoplatform of Au nanorods (NRs), mesoporous silica, HA and Arginylglycylaspartic acid (Au-NRs-mSiOeceptors .Other parts of the work specify the treatment for cancer stem cells (CSCs) in triple-negative breast cancer (TNBC). To precisely target CD44 receptor-overexpressing cells, together with CSCs, a pentameric nanocomplex (PNC), comprising Au-NPs and DOX conjugated to thiolated HA and PEG, DNA CD44 aptamer, was utilized. At a pH of 4.7, and in the presence of 10 mM glutathione, the most significant in vitro drug release occurred after 8 h. The PNC was nearly ten times more potent when compared with DOX alone .To achieve successful combined photothermal chemotherapy, it is essential to ensure that the photothermal agent is delivered specifically to the tumor and the chemotherapeutic drug is released in a controlled manner. To address these objectives in a single study, a novel nanoplatform called Au-NRs-HA-FA, which incorporates Au-NRs, HA, and FA was developed for breast cancers. The nanoplatform can chemically load DOX through a pH-sensitive hydrazone linkage with around 7.1 wt.% of DOX loading. The designed nanoplatform proved to have good biocompatibility. The nanoplatform decorated with FA showed a notably higher capacity to deliver Au-NRs and DOX to MCF-7 cells through folate receptor-mediated endocytosis. This approach efficiently induced cell apoptosis under NIR irradiation. In vivo experiments showed that the combination of photothermal therapy and chemotherapy resulted in the complete elimination of tumors without causing severe side effects to normal tissues .In another report, the highly potent cytotoxic agent SN38 was conjugated to HA, which was then deposited on the surface of Au-NPs through electrostatic interactions. A loading capacity for SN38 loading of 17.4% was observed and in vitro release studies showed that drug release under acidic conditions was faster when compared with physiological pH environments. The cytotoxicity study on MUC1 positive HT29, SW480 colon cancer cells and MUC1 negative CHO cells indicated that the designed potent hybrids had a higher toxicity on HT29 and SW480 cell lines than on CHO cells .A new approach was developed to synthesize hollow silica nanoparticles (HSNs) containing Au nanocomposites (Au-HSNs) without the use of surfactants, which advances their photothermal properties. The even distribution of Au-NPs in the HSN and presence of a dopamine-hyaluronate (DA-HA) coating on Au-HSN was verified. Under near-infrared irradiation (NIR), the Au-HSN/DA-HA exposed exceptional endocytosis in cancer cells without inducing cytotoxicity .In another study, a novel strategy was discovered to deliver cisplatin selectively to tumors by conjugating it to Au-NPs coated with HA, and to enhance its therapeutic efficacy using laser treatment. In vitro studies demonstrated that the designed systems were more cytotoxic than free cisplatin, and in vivo experiments showed significant antitumor efficacy when combined with near-infrared laser treatment .Zhang et al. reported that Poly (glycidyl methacrylate) (PGMA) microspheres, Au-NPs, and HA produced nanocomposites for precise photothermal application. The PGMA microspheres were obtained using emulsifier-free emulsion polymerization followed by amination, and Au seeds were adsorbed via chelation to obtain Au-PGMA. Further, to target cancer cells specifically and reduce side effects in normal cells, HA was conjugated on the surface of Au-PGMA. The Au-PGMA-HA displayed superior selective targeting toward cancer cells and excellent photothermal outcomes, resulting in three times the therapeutic effectiveness against cancer cells when compared to normal cells .Overcoming multidrug resistance (MDR) in cancer therapy is a significant challenge. To address this issue, a non-viral gene delivery system using HA-conjugated and PEI-modified PEGylated Au nanocages (Au-NCs) loaded with microRNA-21 inhibitor (anti-miR-21) was developed to enhance the efficacy of DOX. In vitro studies showed the HA/anti-miR-21/PP-Au-NC system increased intracellular DOX accumulation and sensitized DOX-resistant HCC cells (HepG2/ADR cells) by upregulating PTEN protein expression and downregulating P-gp protein expression. Additionally, mild NIR led to hyperthermia of the HA/PP-Au-NCs, further improving the therapeutic effects. Moreover, the HA/anti-miR-21/PP-Au-NCs system showed good biocompatibility, highlighting its significant role as a new strategy for cancer treatment with MDR .3, exhibited a size-reducible property triggered by hyaluronidase and high accumulation with homogenous intra-tumor distribution. The construct was successful in reducing tumor growth by 95.3% and inhibiting the growth of lung metastasis by 88.4%, demonstrating its potential as an effective strategy for improved antitumor therapy [The effective exploitation of the EPR result of tumors requires careful consideration of NP sizes. Larger particles have good retention but poor penetration while smaller ones have the opposite effect. Size-reducible NPs have been developed to address this issue, although the primary size and complex tumor microenvironment continue to limit their distribution. To overcome these challenges, size-reducible nanoplatforms using hyaluronidase-degradable HA and cationic bovine serum albumin (CBSA) protected Au-NCs have been obtained. The ratio of HA to Au-NC-CBSA, Au-NC-CBSA-HA can be adjusted and varying initial sizes designed so as to evaluate the pharmacokinetic profiles and tumor-targeting efficiencies. Furthermore, the Au-NC-CBSA-HA platform. with a size of 200 nm, can be utilized to load paclitaxel (PTX) and indocyanine green (ICG) for chemo-photothermal therapy, as well as nitric oxide (NO) to enhance drug delivery and modulate the tumor microenvironment. The final construct, Au-NC-CBSA-PTX-ICG-HA-NO therapy .In other research, a versatile nanoplatform was fabricated by functionalizing gold nanorods (Au-NRs) with HA (containing hydrazide and thiol moieties). Then, 5-aminolevulinic acid (ALA), Cy7.5 and anti-HER2 antibody were chemically conjugated onto the HA moiety for PDT, fluorescence imaging and active targeting, respectively. This nanoplatform remarkably enhanced the cellular uptake of Au-NR-HA/ALA/Cy7.5-HER2 in vitro. The scheme and respective mechanisms are displayed in Another study designated the development of a light-responsive drug delivery system based on host-guest chemistry. This system consists of a gold nanorod (Au-NR) that generates plasmonic heat upon NIR exposure, and a layer of HA immobilized to the Au-NR via functionalization with the macrocycle. It further released a retinoic acid (RA) derivative, a molecule important in tissue development, homeostasis, and cancer treatment. The formulation and the bioactivity of the released RA was demonstrated in a reporter cell line expressing luciferase controlled by the RA receptor .The dual combination of chemotherapy and photothermal therapy has proved a promising approach for treating cancer. To achieve a multifunctional conjugated system, oxidized HA decorated dihydroxyphenyl/hydrazide biofunctionalized hydroxyethyl chitosan (DHHC)-Au-NR is used. The DOX was loaded onto the conjugate resulting in a drug loading content of 5.1%. The DOX-loaded multifunctional conjugated system showed good stability in neutral aqueous solutions and had pH-responsive drug release. In vitro studies demonstrated that the conjugate was efficiently internalized by MCF-7 cells and had synergistic therapeutic effects .Another study reported on a nanosystem which is highly responsive to multiple stimuli and can deeply penetrate tissues, co-delivering poly(amidoamine) (PAMAM) stabilized AuNPs and pH-responsive DOX prodrug (PD conjugate) incorporated into a HA-based nanoshell. By leveraging the different properties of the PD, Au-NPs, and HA nanoshell, its feasibility was demonstrated both in vitro and in vivo, achieving remarkable intratumoral penetration and a synergistic radio-chemotherapeutic effect .It is important to note that combining multiple therapeutic modalities that utilize distinct mechanisms for eliminating tumors has become an encouraging approach for treating cancer. Focusing on such aspects, an innovative platform was developed using chemo-photothermal therapy of breast cancer, which utilizes an aldehyde/catechol-functionalized HA (DAHA) and hydroxyethyl chitosan (HECS) decorated Au-NR. The resulting nanoplatform proved to have 4.1% of DOX content and exhibited pH/NIR drug release behaviors. The designed nanoplatform was effectively taken up by MCF-7 breast cancer cells and displayed superior efficacy in eliminating cancer cells when compared to the individual therapeutic modalities . The sch2), with a gatekeeping system composed of an HA layer and Au-NPs. Whilst pSiO2 served as the drug carrier, the HA and Au NPs acted as the gatekeepers to control drug release. The amoxicillin (Amox) loading content was 18.2% and the release rate was regulated by redox-induced breaking of S-Au bonds and enzymatic degradation. The pSiO2-Au/HA composite exhibited remarkable photothermal conversion efficiency and repeatability [Chen et al. developed a new drug carrier based on porous silica  with worm-like nanostructures as a theranostic system for efficient photodynamic therapy (PDT) under light irradiation. To achieve this, citrate-stabilized Au-NPs were assembled using HA and hydrocaffeic acid (HA-HCA) conjugates as templates. The photosensitizers (PSs), and tumor-targeting ligands were integrated onto the surfaces of the Au-NCs and were highly selective, showing notable phototoxicity, even at low PS concentrations, when exposed to laser irradiation .Generally, the Au-core mesoporous silica shell (Au-MSS) offers a versatile and promising approach in cancer photothermal therapy. Nonetheless, restricted half-life in the bloodstream and the low specificity towards tumor tissue have constrained the potential use in further applications. To address such issues, in this study, D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) and HA were conjugated to improve the biological performance of Au-MSS. Furthermore, the Au-MSS functionalization improved the hemocompatibility and selectivity of the nanomaterial towards cancer cells. Moreover, it successfully induced the death of HeLa cancer cells through an on-demand photothermal effect .Li et al. reported on a small-sized nanocomposite for cancer therapy and diagnosis. The nanocomposite was composed of chlorine e6 (Ce6) integrated Au nanoclusters (NCs) (Au:Ce6 NCs), HA, DOX, and FA. The FA conjugation of the nanocomposite further enhanced the cellular selectively target, while its pH-responsive nature controlled the release of DOX for tumor chemotherapy. The nanocomposite displayed good biocompatibility, stability, and loading capacity for Ce6 and DOX were 11.3 and 10.00%, respectively. The combination of chemotherapy and PDT in the nanocomposite resulted in significant cancer cell death upon exposure to laser irradiation .The presence of cancer stem cells (CSCs) represents a foremost challenge to the effectiveness of existing cancer treatments, as non-CSCs can instinctively convert into CSCs, leading to treatment failure and tumor recurrence. Therefore, developing effective strategies to eradicate CSCs is crucial. To solve these issues, a CSC-specific, RA-loaded Au-NS with dendritic polyglycerol (Au-NSs-dPG) nanoplatform was developed for efficient CSC eradication. The designed system exhibited excellent biocompatibility and effective CSC-specific multivalent targeting through HA decoration on the bioinert dPG’s multiple attachment sites. Furthermore, RA-induced CSC differentiation combined with PTT yielded high therapeutic efficacy in a synergistic inhibitory manner, suppressing breast CSCs and tumor growth. Moreover, the expression of stemness genes and CSC tumorsphere development were notably reduced. In vivo, the nanoplatform effectively eliminated tumor growth and CSCs, indicating higher anticancer activity and effective CSCs suppression . The sch2. This platform unveiled visible-light absorption at 668 nm and robust NIR absorption at 800–1000 nm. The CAT/THA-Ce6-sAu-NRs were able to easily accumulate in CD44-overexpressing MDR breast cancer cells via CD44-HA recognition. Additionally, CAT catalyzed the decomposition of endogenous H2O2 to generate O2, thus mitigating hypoxia and ensuring high PDT efficiency [In recent work, Ce6-adsorbed small Au nanorods (Ce6-sAu-NRs), that can activate photothermal and photodynamic effects through NIR/visible light, were produced. The Ce6-sAu-NRs were decorated with biological macromolecules, such as thiolated HA and catalase (CAT), to enable targeting of CD44 and self-supply of Oficiency . The schA very recent report involves the advance of a pH/NIR dual stimulus-responsive delivery system fabricated using polydopamine (PDA) mediated Au with HA, loaded with DOX drug (PDA-Au-HA/DOX), having loading content of around 10.00 wt.%, to targets tumors. The developed system is coated with HA, which endows it with tumor-targeting capabilities by binding specifically to the CD44 receptor, which is overexpressed in various tumor cells. The PDA and Au nanoshells exhibited excellent photothermal performance under NIR irradiation, destroying tumor cells and accelerating the release of DOX . OverallIn 2018, HA and AgNP combinations which exploit the electrostatic interaction between negatively charged HA molecules and positively charged AgNPs, followed by ultrasonication-induced assembly, were introduced. The cell line studies for HA-Ag-NPs exhibited anti-leukemic activity via ROS overproduction compared to AgNPs alone. Furthermore, the outcomes indicated that HA-Ag-NPs significantly inhibited leukemia cell viability by inducing apoptosis via specific binding of HA with CD44 receptors that were overexpressed on the cell surface. Therefore, HA-Ag-NPs represent a novel approach for leukemia treatment that takes advantage of altered redox conditions in cancer cells and reduces systemic toxicity. These findings provide valuable insights into the design and improvement of leukemia-specific chemotherapy .Another study involved using HA as a gel-forming agent, and Amanita muscaria extract was utilized as the capping agent during the synthesis of Ag and ultra-small iron oxide to obtain Fe-Ag-NPs for synergistic anticancer properties. The potential of the HA/Fe-Ag gel for localized cancer treatment was demonstrated through cytotoxicity studies conducted on both 2D and 3D HeLa cell cultures. The gel formulation utilized HA as a gelling agent and it was observed that HA improved the transportation of the active components within HeLa spheroids, thereby enhancing their effectiveness. These findings suggest that the HA/Fe-Ag NPs have potential as a beneficial approach for cancer treatment .In order to overcome the limitations of “single-strategy” therapy in real body internal environments, Liu et al. utilized HA-modified Ag-S-nitrosothiol core-shell NPs using  for synergistic therapy, based on a combination of PTT and nitric oxide (NO)-based chemotherapy. Under NIR, the Ag core generated cytotoxic heat leading to cancer cell apoptosis. In addition, the S-nitrosothiol polymeric shells responded to NIR and heat by releasing free NO at high concentration, which induced NO-based chemotherapy. The efficacy of the photothermal and NO-based chemical synergistic therapy in targeting tumors was demonstrated through both in vitro cytotoxicity assays and in vivo experiments conducted on mice with tumors . OverallThe use of targeted photothermal therapy (PTT) in cancer treatment can enhance therapeutic outcomes while minimizing side effects. Nevertheless, incorporating additional functionality comes at the cost of increased synthetic steps, toxicity issues, and complex in vivo behavior effects. To address such difficulties, the one-pot method is used to produce HA/Pt tumor-targeted systems. Further, in vitro experiments validated that CD44-overexpressing cancer cells were internalized more effectively than non-targeted alginate acid-Pt nanoparticles (AA/Pt). Similarly, in in-vivo studies HA/Pt accumulated more in CD44-overexpressing tumors than AA/Pt, and proved to have superior efficacy in inhibiting tumor growth through PTT .1O2 due to the involvement of CDs photosensitizers. The loaded Pt NPs enhances photodynamic therapy under hypoxic conditions by producing oxygen via catalase-mimicking activity. Moreover, it produces OH and O2− for catalytic therapy, due to peroxidase and oxidase-mimicking actions [It is important to mention that developing a nanoplatform that can effectively target hypoxic tumors using PDT is critical in contemporary cancer research. Thus, in this work a ROS-generator, called HA-modified Pt NPs/carbon dots-loaded mesoporous silica (HA-PCD), was designed. The HA-PCD is composed of Pt NPs and carbon dot (CD)-loaded dendritic mesoporous silica nanoparticles (DMSNs), further modified with HA. When exposed to 635 nm laser irradiation, HA-PCD produces  actions .Another work described novel multifunctional drug delivery systems developed using, Pt, Pd, glucose oxidase (GO) and HA to obtain Pd-Pt-GO/HA, which addressed the low efficiency and potential side effects to normal tissues associated with GO-mediated starvation therapy. The Pd-Pt-GOx/HA system specifically targets CD44-overexpressed cancer cells and possesses intracellular Hyase-responsive GO, catalase (CAT), and peroxidase (POD)-like activities as well as glutathione (GSH) oxidation capacity, significantly enhancing therapeutic efficacy and biosafety. The differential uptake of Pd-Pt-GO/HA by cancer cells and normal cells demonstrated that the reactive oxygen species (ROS) induced cell apoptosis. Furthermore, in vivo experiments demonstrated the excellent treatment efficacy of Pd-Pt-GO/HA on 4T1 and h22-tumor-bearing mouse models . The repZhang et al. developed a nanosystem for photothermal therapy (PTT) and antioxidant therapy by constructing Pd-Se-HA nanosystems. The selenium (Se) NPs and Pd NPs were integrated into the core-shell structure, where the Pd NPs showed photothermal effects. Further, HA was bonded to the surface of the nanosystem to provide targeting functions and to form Pd-Se-HA nanosystems. In vitro studies demonstrated good photothermal effect, -OH scavenging ability, effective inhibition of macrophage infiltration, ROS production, and cytokine-mediated inflammation. In addition, after 15 days of treatment, the Pd-Se-HA almost completely stopped the inflammatory response in the joints of mice with an induced RA model and stopped joint degradation .2-HA. The deposition of Pd NPs creates Schottky junctions that separate electron-hole pairs, raising the competence of toxic ROS production during SDT. The MnO2 degrades within the tumor microenvironment (TME), and the Mn2+ ions catalyze the Fenton-like reaction generating •OH from H2O2. The BTO-Pd-MnO2-HA incessantly consumes glutathione (GSH) and produces O2, which improves SDT and chemodynamic therapy (CDT) efficiency. The BTO-Pd-MnO2-HA offers a multistep. improved SDT process that is activated by TME decomposition, targeted by HA, and amplified by Pd depositions [To develop new inorganic sonosensitizers for sonodynamic therapy (SDT), two primary goals should be noticed, such as increase in the formation of ROS and decrease in ROS elimination. In this work, new SDT systems were designed by using unique combinations of barium titanate oxide NPs, Pd, manganese dioxide and HA to produce BTO-Pd-MnOositions . To concA water-based two-step method was used to produce hybrid combinations of superparamagnetic iron oxide NPs, chitosan and HA loaded with curcumin drug (SPION-CCh-HA-Cur). The SPIONs have a core size of slightly above 10 nm and the designed hybrid systems exhibit high magnetic properties, making them suitable for use as MRI contrast agents. Furthermore, biological studies showed that hybrid systems can be easily internalized into cells and did not exhibit cytotoxicity at the tested concentration .In another work, HA-modified SPIONs were developed and placed upon NIR. The HA-SPIONs generate heat rapidly and in-vitro studies showed that HA-SPIONs revealed noteworthy explicit cellular uptake and accumulation in CD44 HA receptor-overexpressing MDA-MB-231 cells. Furthermore, improved magnetic resonance imaging (MRI) and photothermal ablation, both in vitro and in vivo, demonstrated substantial photothermal effects specifically targeting CD44 HA receptor-overexpressing breast cancer .3O4-PB). The resulting Fe3O4-PB-HA-BSA-ZCIS QDs, denoted as FPPBH, demonstrated good biocompatibility and better adsorption in the NIR region. In vitro studies revealed specific uptake of FPPBH by CD44 overexpressed HeLa cells when an external magnetic field was applied. In vivo NIR fluorescence and magnetic resonance imaging demonstrated the high accumulation of FPPBH at the tumor site due to the exceptional CD44 receptor/magnetic targeting ability. The tumor was successfully ablated in nude mice after intravenous FPPBH injection and treatment with an external magnetic field, which led to a tumor growth inhibition rate of more than 89.95% when the tumor was exposed to NIR light [Other work reported conjugation of hyaluronic acid (HA) and bovine serum albumin (BSA)-modified zinc copper indium sulfide quantum dots (ZCIS QDs) onto the surface of polyethyleneimine (PEI)-coated iron oxide-Prussian blue NPs , which is ideal for effective chemotherapy. Lastly, the in vivo antitumor efficacy of these hybrid systems was demonstrated in mice, confirming their substantial therapeutic potentials .Another significant investigation reported that a novel magnetic nanovehicle was developed using HA conjugated iron oxide (IONPs) for targeted delivery of chemotherapy drugs to tumor areas with external magnetic field guidance. Moreover, the IONPs were capable of carrying homocamptothecin (HCPT) model drug, and 75% of HCPT was encapsulated in the HA-IONPs. The in vitro and in vivo experiments demonstrated remarkable magnetic tumor targeting and effective tumor cell ablation. Notably, no systemic toxicity was observed, highlighting the potential clinical translatability of the designed nanovehicle as a magnetic field responsive platforms for targeted delivery applications .Zheng et al. developed nanoplatforms comprised of HA-SPION micelles, loaded with docetaxel (DTX) drug, with a loading efficiency of 10.9%. The results of cellular uptake studies demonstrated that MDA-MB-231 cells were internalized via CD44 receptor-mediated endocytosis, due to the existence of a magnetic field and evidenced good MRI potential. Additionally, the micelles achieved superior localized photothermal ablation attainment in MDA-MB-231 cells, demonstrating their potential as effective photo-absorbers in photothermal therapy .The overall scheme to obtain micelle-loaded DTX drug and the dual tumor targeted therapies are shown in A new nanoplatform with synergistic chemo-photothermal therapy was designed using magnetic polydopamine (MPDA), HA-MTX for PTT. The nanoplatform proved to have excellent biocompatibility and photothermal conversion efficiency suggesting potential for photothermal therapy, as well as improved cellular uptake and drug release. Additional studies conducted both in vitro and in vivo showed that MPDA-HAMTX with DOX added had preferential tumor accumulation, improved specificity to target tumor cells, pH- and laser-responsive release, and a high tumor cell-killing efficiency .Other research studies revealed HA-PEGylated magnetic nanoparticles (HA-PEG-MNPs) prolonged the circulation time of mitoxantrone (MTX) and targeted specific tumor cells. The MTX loading efficiency was around 87.7%, the release of MTX from HA-PEG-MNPs was mainly inhibited by amide linkages, and HA-PEG-MNPs remained stable in physiological conditions for up to 8 days. In addition, HA-PEG-MNPs could bind to the receptor-binding site and internalize into tumor cells, proving significant induction of apoptosis in MDA-MB-231 cell lines .2 and validated with an LND loading efficiency of 6.3%, while APTES amino groups were used to attach HA. Additionally, it was conjugated with lactoferrin (Lf)-bearing carboxylic groups on the HA, which led to the development of surface-modified pH-sensitive alloy-drug nanoconjugates known as SPANs. These SPANs demonstrated exceptional heat generation upon exposure to magnetic fields and NIR. Due to the leaching of Fe and Pt contents, SPANs were capable of generating ROS in the U87MG cell line, thereby enhancing their therapeutic effects. The in vivo results confirmed enhanced uptake of SPANs in the brain after intranasal administration with improved nasal and mucus penetration due to the presence of Lf [Another report described utilization of FePt alloy nanoparticles with precise sizing, which were subsequently treated with (3-Aminopropyl) triethoxysilane (APTES) to modify their surfaces. Through a pH-sensitive hydrazone bonding process, lenalidomide (LND) was covalently bonded to FePt-NHce of Lf .3O4 NPs using PEI and mPEG for targeted MRI of pancreatic cancer. The cellular uptake analysis results showed that MIAPaCa-2 cells, which overexpress the CD44 receptor, were specifically internalized by HA-Fe3O4 NPs. Therefore, the developed system could serve as an effective nanoprobe for the MRI of pancreatic cancer cells [Luo et al. developed stable and cytocompatible HA-Feer cells .3O4 NPs coated with porous carbon (PC), followed by amine terminated groups which were subsequently modified with HA for targeted tumor treatment. The designed system unveiled exceptional biocompatibility and efficient photothermal transformation capability, and the porous structure allowed for a high DOX drug loading capacity of around 27% and intelligent drug release, making it a multifunctional nanodrug delivery system. In vivo T2-weighted MR imaging displayed the accumulation of nanocarriers in the tumor. Both in vitro and in vivo studies were conducted to confirm the efficacy of the system [Another work involved a solvothermal method to create Fee system .3O4 tagged with HA to load DOX were reported on, for improved T1-weighted MR imaging and chemotherapy of cancer cells that overexpress CD44 receptors. The reported LDH-Fe3O4-HA demonstrated a 10-fold increase in r1 relaxivity compared to Fe3O4 NPs and proved to have57.65% DOX loading capacity. The designed LDH-Fe3O4-HA demonstrated pH-responsive release behavior, and showed targeted tumor inhibition effect in vitro. The in vivo result indicated improved tumor penetration and significantly enhanced MR imaging ability [In other work layered double hydroxides (LDHs) conjugated Fe ability .3O4 had a significant impact with good antitumor efficacy for MDR cancer therapy with minimal cardiotoxicity. Furthermore, PC/HA-DOX-Fe3O4 was able to deliver DOX to a xenograft tumor, and could concentrate into the tumor cells in in vivo studies [In another study, through a simple process, dual-stage carcinoma cell-targeting systems for DOX delivery were witnessed. The interaction between the coated phosphatidylcholine PC/HA surface and embedded DOX-Fe studies .3O4 with an appropriate size for magnetic hyperthermia therapy and targeted CD44 overexpressing cancer cells. The deigned system unveiled excellent colloidal stability and low cytotoxicity towards L929 cells. Further, Fe3O4-HA NPs preferentially targeted MDA-MB-231 cells with a 4-fold higher uptake than L929 cells. Additionally, the heat generation capability of Fe3O4-HA NPs under different permissible magnetic fields indicated an intrinsic loss power (ILP) value of Fe3O4-HA NPs of about 3.5 nHm2/kg, which was about 25-fold higher when compared with bare Fe3O4 NPs [Soleymani et al. substantiated a simple one-pot system for synthesizing HA-coated Fee3O4 NPs .Another study explored multifunctional nanocarriers for cancer therapy using a combination of magnetic and photothermal therapies. The cisplatin-loaded NIR-responsive PLGA magnetic nanoparticles were coated with HA and labelled as HA/PMNPc. The PMNPc, encapsulating oleic (OA) modified iron oxide nagnetic NPs (IOMNP), allowed for magnetic targeted drug delivery. By varying the amount of cisplatin it was possible to obtain loading capacity differences from 5.3 to 18.00%. The incorporation of HA to PMNPc resulted in a much higher intracellular uptake efficiency and active targeting of U87 cancer cells. In a xenograft tumor model in nude mice, treatment with HA/PMNPc via tail vein injection, resulted in the lowest tumor growth rate. The dual-targeting capability of HA/PMNPc makes it a promising multifunctional platform for effective cancer therapy against U87 glioblastoma cells .One of the main drawbacks involved in chemotherapy is inadequate adhesion of drugs in tumors, leading to the failure of cancer cell growth prevention. To enhance such drawbacks, a highly efficient nanocarrier, designed by modifying iron oxide nanoparticles (IONPs) with a tumor-targeting peptide c(RGDyK) and hyaluronidase (HAase) on the surface, exhibited DOX loading capacity of around 21.7%. The resulting nanocomplex bound to integrin αvβ3 to target the tumor and penetrated intensely into the tumors by degrading the highly expressed HA in the tumor extracellular matrix (ECM). In vitro, c(RGDyK)-HAase-IONP carrying DOX showed good biostability and a preferred drug release profile at low pH. After intravenous injection in MC38 tumor-bearing mice model, c(RGDyK)-HAase-IONP exhibited a 2.5 times higher tumor-targeting effect .3O4 magnetic nanoparticles. In-vitro release behavior for DOX was evaluated at two different pH levels: simulated human blood fluid (pH = 7.4) and simulated cancer fluid (pH = 5.6). Strong pH dependence was pbserved. The nanocarrier’s pH-sensitive release performance resulted in a higher DOX release at pH = 5.6  than at pH = 7.4 . Moreover, the results demonstrated that the DOX release mechanism from the nanocarrier was guided by Fickian diffusion kinetics [In another research work, a magnetic nanocarrier sensitive to pH was developed for the delivery of DOX, through grafting HA/β-cyclodextrin onto Fekinetics . Overall2+ in tumor cells, leading to dissociation of the Zn2+ DOX complex and controlled release of DOX. The use of the OMCNP-based system can induce hyperthermia and promote the release of DOX when exposed to NIR irradiation. When combined with targeted chemo-photothermal therapy, this approach yielded better results than either single chemotherapy or photothermal therapy alone [In order to enhance therapeutic effectiveness, a new system was designed using PEG-modified oxidized mesoporous carbon nanospheres (OMCNPs) loaded with DOX drug. To target lung cancer cells, the OMCNPs were modified with HA. Furthermore, zinc oxide quantum dots (ZnO QDs) were added to not only cap the OMCNP, but also to chelate with DOX, resulting in 52% loading content. Upon cellular uptake, the pH-sensitive ZnO lids dissolved to Znpy alone . The schIn another report, a bioreducible carrier for siRNA delivery, was created by conjugating Zn (II)-dipicolylamine onto HA (HA-DPA(Zn)) to coordinate with siRNAs and create stable formulation in the presence of zinc ions. The siRNA formulated with this carrier was efficiently taken up by U87MG cells and released the incorporated siRNAs in response to reduction signals. In vitro studies demonstrated that siRNA formulated HA (HA-DPA(Zn)) effectively silenced genes with minimal toxicity. It also proved to have a prolonged circulation time in the bloodstream, enhanced accumulation in the tumor site, and remarkable antitumor efficacy in a U87MG tumor-bearing mouse model, without triggering any organ toxicity .Another research study conjugated zinc oxide (ZnO) through a co-precipitation method with HA to obtain (HA-ZnO). The conjugated system was then modified with ginsenoside Rh2, to obtain Rh2-HA-ZnO. The designed Rh2-HA-ZnO exhibited anti-cancer effects on three different cancer cells, namely, A549 lung cancer, HT29 colon cancer, and MCF7 breast cancer cells. Additionally, intracellular ROS were observed in all three cancer cell lines .In the treatment of non-small-cell lung cancer (NSCLC), radiotherapy (RT) is a key approach, but there is a critical need to amplify its negative effects on tumors through the development of new treatment modalities. To address such problems, Wang et al. prepared block copolymer micelles comprised of PEG and polycaprolactone (PEG-PCL) comprising HA manganese and zinc (Mn-Zn) ferrite magnetic nanoparticles (MZF). Furthermore, micelles with HA-modified MZF resulted inMZF-HA for specific targeting of CD44 highly expressing tumor cells, such as A549 (human lung adenocarcinoma cell line). In the A549 subcutaneous tumor xenografts model, the MRI proved the enhancement of MZF-HA in the tumor, and hypoxia immunohistochemistry analysis (IHC) confirmed enhanced tumor oxygenation after HT. Furthermore, there was a 49.6% decrease in tumor volume, compared to a 58.8% increase in the untreated group . The outIn another work, biodegradable NPs which can target tumors were developed for photothermal therapy (PTT) against human cancer cells that overexpress CD44. The zinc (II) phthalocyanine-based photosensitizer (ZnPc) was loaded to PLGA-HA, and exhibited high stability and good biocompatibility. Upon 808 nm irradiation, the ZnPc-PLGA-HA induced a photothermal effect and promoted cellular uptake by CD44-overexpressed A549 and HT29 cells, leading to enhanced photothermal efficacy. Moreover, the ZnPc-PLGA-HA was able to ablate the tumor of nude mice upon laser irradiation . The schDespite significant progress in breast cancer treatment, the challenge of addressing the aggressive nature of TNBC is considered a major obstacle. Thus, to deliver a solution, PEI assisted HA tagged with ceria (PEI-HA-Ce) can be used as a therapeutic agent, and has demonstrated significant anticancer effects and is responsible for the generation of ROS for MDA-MB-231 TNBC cells. The designed PEI-HA-Ce demonstrated efficient endocytosis, resulting in MMP loss and successive release of Cyt c from the mitochondria. This led to the activation of caspases-3 and -9, while also decreasing levels of Bcl-2. Treatment with PEI-HA-Ce led to irreversible nuclear chromatin condensation .2 NPs catalyzed the production of oxygen from hydrogen peroxide through the cycling of cerium valency, thus enhancing both PTT and PDT. This strategy successfully improved the hypoxic microenvironment of the solid tumor. Additional results verified that ICG-PEI-HA/CeO2 increased ICG uptake at the cellular level, induced apoptosis of tumor cells, and increased in vivo bioavailability of ICG at the tumor site [Other work resulted in a dual-targeted drug delivery system for solid tumors by using a pH-sensitive polymer and an inorganic nanozyme. The core of the PEI polymer was loaded with indocyanine green (ICG) by electrical charge adsorption. Once delivered to the tumor site, the CeOmor site . The sch3O4) for targeted delivery incorporated with cerium oxide (CeO2) on the surface of NPs to generate ROS in the tumor environment, inducing oxidative stress and selective killing of cancer cells. Additionally, HA was used to coat the CeO2 surface and target CD44-overexpressing tumor cells, while natZr was chelated on the Fe3O4-CeO2 surface to enable labeling with the radioisotope 89Zr. Furthermore, good dispersibility of the HA coated NPs showed that CeO2 generated ROS and targeted delivery [Another work depicted utilization of SPIONPs  to produce HA-CeO2-MOF and the resulting PDT treatment are shown in 2 catalyzes H2O2 to produce O2, resolving hypoxia issues, and HA targets the CD44 receptor expressed on tumor cell membranes. When incubated with HA-CeO2-MOF under laser irradiation, the growth of tumor cells 4T1 and MCF-7 was distinctly controlled, while the survival of normal cell LO2 was nearly unchanged. Importantly, HA-CeO2-MOF was effectively aggregated within the tumor area 12 h after injection and remarkably inhibited tumor growth under laser irradiation [Although photodynamic therapy (PDT) has shown better results in cancer treatment, its effectiveness has been limited by hypoxic tumors, poor targeting, and photosensitizer (PS) aggregation. To address all these drawbacks, HA-modified CeOadiation .2) to address existing challenges. By using CeO2 NPs, 5-HT and HA mediated to achieve dual targeting effects of MPO and the macrophage CD44+ receptor, the HA-5-HT-CeO2 was able to locate the inflammatory site and eliminate O2, H2O2, and ROS. This strategy successfully repaired the intestinal epithelial barrier by specifically targeting inflammatory factors. In vitro pharmacodynamic investigations and animal models of acute colitis indicated that HA-5-HT-CeO2 demonstrated superior efficacy in reducing inflammation and treating ulcerative colitis compared to conventional drugs [Ulcerative colitis (UC) is a challenging chronic nonspecific inflammatory bowel disease characterized by rapid progression. The high expression of myeloperoxidase (MPO) in colonic ulcers of UC patients results in an abundance of macrophages and ROS. In this respect, Gao et al. developed an electrostatically assembled MPO targeting HA/serotonin/(5-HT) ceria nanoenzyme  and other relevant protocols is necessary for industrial-scale productions.Quality Control and characterization: Industrial production requires stringent quality control measures to ensure consistency and reproducibility. Robust analytical methods should be established for accurate characterization, including size distribution, surface chemistry, and drug-loading efficiency. Furthermore, standardization of characterization techniques is essential for batch-to-batch consistency and comparability.Scalability of functionalization: HA-modified M-NPs can be functionalized with various ligands, targeting moieties, or therapeutic agents to enhance their specificity and efficacy. Thus, developing scalable methods for functionalization and achieving uniform surface handling are critical challenges. The biocompatibility of different functionalization strategies with large-scale production needs to be evaluated.Manufacturing partnerships and collaboration: Establishing collaborations between research institutions, pharmaceutical companies, and manufacturing facilities is crucial for the successful transition to industrial application. Collaboration can help leverage expertise, resources, and infrastructure required for large-scale production, quality control, and regulatory compliances.Overall, the clinical to the industrial transition of HA-modified M-NPs in cancer treatment is a complex process that involves optimization of manufacturing processes, cost considerations, stability, regulatory compliance, quality control, and collaborations. Addressing these challenges will facilitate the translation of this promising technology into practical and accessible solutions for cancer patients.Targeted drug delivery: HA modification of M-NPs and with other substituents enables targeted drug delivery to cancer cells. Future research can focus on developing multifunctional NPs that encapsulate other therapeutic agents, such as chemotherapeutic drugs and small interfering RNA (siRNA). The incorporation of targeting ligands or antibodies on the surface could enhance specificity towards cancer cells, minimizing off-target effects.Imaging and diagnosis: HA-modified M-NPs can serve as excellent imaging agents for cancer diagnosis. The unique optical, magnetic, and photoacoustic properties of M-NPs can be exploited to develop imaging probes for early cancer detection, precise tumor localization, and monitoring of therapeutic responses. Future research should explore the integration of imaging modalities with therapeutics, allowing simultaneous diagnosis and treatment.Photothermal therapy: M-NPs possess photothermal properties, converting light into heat, which can be utilized for targeted cancer therapy. HA modification enhances tumor accumulation and internalization of M-NPs, making them an ideal platform for photothermal therapy. Future studies can focus on optimizing NP design, selecting appropriate light sources, and investigating the synergistic effects of combining photothermal therapy with other treatment modalities.Immunotherapy developments: HA modification of M-NPs holds potential in modulating the tumor microenvironment and enhancing immunotherapy approaches. The immune response can be stimulated by incorporating immune modulators, such as cytokines or immunomodulatory agents, onto the surface of NPs. Moreover, M-NPs can act as adjuvants to promote antigen presentation and improve the efficacy of cancer vaccines. Future research can explore these strategies and investigate the immunomodulatory mechanisms to develop personalized cancer immunotherapies.Theranostic platforms: Integration of diagnosis and therapy into a single platform, known as theranostics, is a promising approach in cancer treatment. HA-modified M-NPs can serve as versatile theranostic agents by combining imaging capabilities, targeted drug delivery, and therapeutic modalities. Future research should focus on developing more multifunctional nanoplatforms that can be precisely controlled and optimized for personalized cancer therapy.Safety and toxicity considerations: As with any novel therapeutic approach, the safety and toxicity profiles of HA-modified M-NPs and other substituents must be thoroughly evaluated. Future research should investigate the long-term effects, biodistribution, and potential adverse reactions associated with the use of these systems in cancer therapy.In conclusion, we summarized past and most recent progress in the application of HA-modified M-NPs and other substituents in various cancer therapy applications utilizing different cancer therapeutic approaches. The abundance of literatures in recent years makes it evident that using HA-modified M-NPs and other substituents as biomaterials to target different tumors is a promising and attractive approach for enhancing cancer therapy. Definitely, there is a dearth of research on the biodistribution, toxicity, and availability of HA-modified M-NPs and other substituents under physiological conditions. A more in-depth study of these parameters is imperative for clinical implementation. Overall, the development of cancer therapeutic systems is a multidisciplinary field that necessitates expertise from a range of fields, such as chemistry, material science and engineering, nanotechnology, and medicine. Therefore, several experts from diverse domains are collaborating to design innovative cancer therapeutic systems that are clinically efficient and have minimal side effects. Such systems are expected to enhance human health in the near future. Some of the future directions listed are below: