Influenza viruses usually cause seasonal influenza epidemics and influenza pandemics, resulting in acute respiratory illness and, in severe cases, multiple organ complications and even death, posing a serious global and human health burden. Compared with other countries, China has a large population base and a large number of influenza cases and deaths. Currently, influenza vaccination remains the most cost-effective and efficient way to prevent and control influenza, which can significantly reduce the risk of influenza virus infection and serious complications. The antigenicity of the influenza vaccine exhibits good protective efficacy when matched to the seasonal epidemic strain. However, when influenza viruses undergo rapid and sustained antigenic drift resulting in a mismatch between the vaccine strain and the epidemic strain, the protective effect is greatly reduced. As a result, the flu vaccine must be reformulated and readministered annually, causing a significant drain on human and financial resources. Therefore, the development of a universal influenza vaccine is necessary for the complete fight against the influenza virus. By statistically analyzing cases related to influenza virus infection and death in China in recent years, this paper describes the existing marketed vaccines, vaccine distribution and vaccination in China and summarizes the candidate immunogens designed based on the structure of influenza virus, hoping to provide ideas for the design and development of new influenza vaccines in the future. Influenza is an acute respiratory infection caused by the influenza virus, which seriously endangers human and animal health and results in death in severe cases . Since tInfluenza virus research in China began in 1952 and led to the establishment of the National Influenza Center in 1957, followed by the establishment of an influenza surveillance network in 2000, focusing on influenza-like case reporting and virus isolation, which has comprehensively improved the overall capacity of influenza surveillance in China. Since 2009, China’s influenza surveillance network has been gradually expanded and improved and now includes 554 sentinel hospitals and 410 network surveillance laboratories covering all provinces, municipalities and autonomous regions in mainland China. Sentinel hospitals report cases of influenza-like illness (ILI) to the China National Influenza Surveillance Information System (CNISIS) and collect respiratory samples. The network laboratories use real-time reverse transcription polymerase chain reaction (RT-PCR) to determine whether the collected samples are positive for influenza virus [With a total population of more than 1.4 billion, the burden of influenza morbidity and mortality in mainland China is high. According to the data on influenza infections and deaths in mainland China from March 2009 to August 2022  and summer epidemics in mid- and low-latitude regions . Among all provinces, January was the peak month of activity, with an average positivity rate of 21.8%, and October had the lowest average positivity rate of 4.37%. In addition, the annual influenza epidemic in mainland China varies according to latitude. Influenza epidemics in high latitude provinces in China are characterized by epidemics in the winter with short durations but strong epidemic intensity, while provinces at middle and low latitudes have weak epidemics but long durations as semiannual epidemics  or year-round epidemics  .According to ILI surveillance and virological data from national sentinel hospitals, Feng et al., calculated the national average rate of influenza-related consultations in 30 Chinese provinces from 2006 to 2015 and found that there are 2.5 consultations per 1000 people, and this peaked at 7.8 consultations per 1000 people during the 2009 influenza pandemic . Gong etIn addition to the severe burden on people’s lives and health, influenza causes huge economic losses to individuals and countries, with indirect economic losses reaching tens of billions of dollars globally each year . China iThe above studies illustrate that influenza epidemics not only cause serious health effects but also impose a significant economic burden, that measures to control influenza epidemics are urgently needed and that vaccination is the most cost-effective means to do so.Influenza vaccination is an effective means of preventing and reducing influenza-associated severe illness and death, as well as reducing the health risks associated with influenza-associated illness and the use of health care resources . The triThe influenza vaccines now approved for marketing in China are trivalent inactivated influenza vaccine (IIV3), quadrivalent inactivated influenza vaccine (IIV4) and trivalent live attenuated vaccine (LAIV3). IIV3 includes both inactivated and subunit vaccines; IIV4 is an inactivated vaccine; and LAIV3 is an attenuated vaccine. As of 14 August 2022, 11 manufacturers have supplied influenza vaccine, and information on specific influenza vaccine manufacturers and their products is shown in Influenza continues to pose a significant threat to public health, and vaccination is currently the most effective response to influenza. Currently, the effectiveness of polyvalent influenza vaccines can be improved by adding adjuvants to stimulate immunogenicity, optimizing means of virus strain prediction and using high doses of injectable vaccine for immunocompromised populations.The inactivated influenza virus vaccine for infants aged 6–35 months is 0.25 mL/dose, containing 7.5 micrograms of each HA antigenic component, and generally requires two doses to achieve immune protection; the inactivated influenza virus vaccine for children aged 3 years and older is 0.5 mL/dose, containing 15 micrograms of each HA antigenic component, and requires only one dose. The standard for the antigenic content of the trivalent live attenuated vaccine is an attenuated virus titer of not less than 6.9 lgEID50  for each of the two subtypes of influenza A virus H3N2 and H1N1 and an attenuated virus titer of not less than 6.4 lgEID50 for the Victoria lineage of influenza B virus, with a size of 0.2 mL/dose, for 3- to 17-year-old children and adolescents aged 3–17 years .The statistics of the batch issue volume of China’s influenza vaccine industry from 2015 to 2020 are shown in According to statistics, the average vaccination rate of influenza vaccine in China was 2.43% from 2014 to 2020, with the lowest rate of 1% in 2018 and 4% by 2020, while according to the Centers for Disease Control and Prevention, 175 million doses of influenza vaccines were distributed in the United States during the 2020 influenza season, with an adult vaccination rate of approximately 48.4%, compared to less than 1 in 10 in China ,20. Due The influenza virus, belonging to the Orthomyxoviridae family, is an enveloped single-stranded negative-sense RNA virus whose genome encodes 11 proteins, namely RNA polymerase subunit proteins , surface glycoprotein hemagglutinin (HA), neuraminidase (NA), nucleoprotein , matrix protein (M1), membrane protein (M2) and nonstructural proteins NS1, NS2 and PB1-F2 , which pInfluenza viruses mutate mainly through antigenic drift and antigenic transformation to evade natural infection and vaccination-induced herd immunity . AntigenThe existing influenza vaccination protection rate is only 40–60%; influenza viruses are prone to mutation; and the effectiveness of the vaccine is further reduced when new influenza virus strains emerge that do not match the vaccine strain ,30. TherHemagglutinin (HA) is the most abundant glycoprotein on the surface of influenza viruses and plays a key role in the process of viral invasion and infection . In termThe HA2 region is a potential research target for a universal influenza vaccine , but sinOne such strategy to increase the immunological advantage of HA stems is to completely remove the HA head region, creating a “headless” HA structure. Headless HA is difficult to develop because it is not stable, and most cross-reactive HA stem antibodies have conformation-dependent epitopes. For example, Wohlbold et al., developed an antigen based on HA stems that induced protection against influenza strains but was not recognized by any antibodies that neutralized the stems due to the lack of the correct conformation of the natural stem structural domain . To addrAnother strategy to induce high levels of anti-stem HA antibodies is sequential immunization with chimeric HA molecules (CHAs), which contain the same HA stems and different HA heads, allowing the induced antibody response to focus primarily on immunizing against the subdominant HA stems. To date, several influenza vaccine platforms have successfully induced HA stem-reactive antibodies in animal models using chimeric HA molecules. Liao et al., demonstrated that a monoglycosylated CHA vaccine with shared H5 as the bulbous head and shared H1 as the stem induced more stem-specific antibodies, had a higher ADCC, better neutralized the viral subtypes under study and had broad protective activity against heterologous influenza viruses  . Kotey eRather than altering the entire head structural domain of HA to produce cHA, these immunodominant antigenic sites in the head should be replaced with sequences of other HA isoforms to produce broader protective potency. For example, Sun et al., replaced the major antigenic site of influenza B virus HA with the corresponding sequence of influenza A virus HA to generate mosaic HA expressed as a soluble trimeric protein and showed that the vaccine was cross-protective against homologous and heterologous influenza B virus strains in a mouse model ; Corder The most widely studied optimized HA protein, called computationally optimized broadly reactive antigen (COBRA), can be used as a recombinant protein or displayed on the surface of viruses or VLPs and has been shown to induce multiple antigenic variants in a variety of animal models, including mice, ferrets and nonhuman primates, with the most widely hemagglutination-inhibiting responses to serum. Reneer et al., constructed an H2 COBRA HA vaccine and tested it in ferrets immunized against H2N3 attack, resulting in vaccinated ferrets exhibiting higher antibody titers and recognizing the highest number of H2 influenza viruses in a classical neutralization assay compared to wild-type H2 HA recombinant proteins ; Huang eNeuraminidase, another major glycoprotein on the surface of influenza viruses, plays an important role in virus transmission by cleaving the viral sialic acid receptor on the host cell membrane to facilitate the release of viral particles and prevent the accumulation of offspring viruses on the cell surface ,54. It iKim et al., constructed an NA VLP vaccine against influenza virus H1N1 pdm09, which induced virus-specific antibody responses after immunization of mice and generated cross-protective immunity against different influenza viruses and further found that sera from mice immunized with this vaccine were cross-protective in young mice . StrohmeMembrane protein (M2) is a transmembrane protein consisting of 96 amino acids divided into extracellular, transmembrane and cytoplasmic regions, and is usually present as a tetramer on the surface of the influenza virus vesicle membrane, forming a proton-selective ion channel regulated by pH, which is activated in an acidic environment at low pH, allowing the proton to be pumped into the viral particle, participating in the processes of viral exfoliation. The extracellular region of the M2 protein, known as M2e, contains only 24 amino acid residues and is exposed on the surface of the viral capsid or on the surface of infected cells and is associated with the assembly of nascent viral particles. Because M2e is highly conserved across different strains and subtypes of influenza viruses, it can induce a cross-protective immune response, making it an attractive target during the development of a universal influenza vaccine. Previous experiments have demonstrated that anti-M2e antibodies bind strongly to M2e bound at the host cell surface and inhibit viral replication and outgrowth, thus producing protection in animals. Due to the weak immunogenicity of M2e itself, many strategies have been used to enhance the immunogenicity of M2e-based vaccines . For example, by increasing the density of M2e epitopes in vaccines to significantly improve immunogenicity and efficacy, Krishnavajhala et al., expressed M2e peptides at high density on Sindbis virus and immunized mice with M2e-specific antibodies that protected them from lethal virulence attack of influenza A virus . FurtherNucleoprotein (NP) is the main component of the nucleocapsid and forms ribonucleoprotein complexes (RNPs) with viral genomic RNA and viral polymerase, which are involved in viral transcription, replication and assembly. NP is the internal protein of influenza virus that induces the production of non-neutralizing antibodies in the host and are also major antigens recognized by cytotoxic T lymphocytes (CTLs) . CTLs exThe basic requirement of the current universal influenza vaccine is to have ≥75% protection against influenza symptoms caused by influenza A and B viruses, and the vaccine should be effective for at least one year in all age groups . HA, NA,A fundamental approach to broad-spectrum influenza vaccine design is to express different conserved epitopes of viral proteins in tandem or fusion, which not only improves vaccine efficacy but also reduces manufacturing time and cost compared to vaccines targeting a single antigenic peptide of the virus. Some relevant studies are available; for example, Golchin et al., designed and synthesized the tandem antigenic protein M2e-HA2, which significantly induced a humoral immune response to influenza virus after immunization of mice, and the viral challenge proved that the tandem protein protected mice from H9N2 influenza virus . FarahmaThe use of nanoplatforms to deliver relevant antigens is a promising approach for the development of novel influenza vaccines. The high density and structural ordering of antigens in nanoparticles promotes antigen recognition by B-cell receptors and triggers an effective cellular and humoral immune response. In addition, nanoparticles have been shown to protect antigens from proteolytic degradation, to improve antigen delivery and to prolong antigen presentation by antigen presenting cells (APCs). For example, Wei et al., constructed a biomimetic influenza vaccine using an apoferritin (AFt) nanocage as a carrier with an internally wrapped NP protein and a surface-coupled HA protein, which produced HA- and NP-specific antibodies with complete protection against lethal infection by homologous and heterologous viruses after immunization of mice, and this biomimetic vaccine suggested a vaccine development strategy . Ma et aVLPs are produced by inserting genes encoding viral structural proteins into plasmid vectors and then transforming or transfecting them into the target expression system. Since the produced VLPs do not contain viral nucleic acids, they are not infectious nor pathogenic, have strong immunogenicity and can stimulate strong humoral and cellular immune responses in the body. Insect cell-baculovirus expression systems are often chosen to produce influenza VLPs, and the resulting VLPs are morphologically similar to natural influenza viruses. For example, Zhang et al., prepared VLPs containing H3N8 equine influenza virus (EIV) HA, NA and M1 proteins by an insect cell-baculovirus expression system, and the hyperimmune serum produced by immunizing horses with the VLPs was injected into mice that were then challenged, showing that the equine hyperimmune serum had good prophylactic and therapeutic effects against H3N8 EIV infection . Li and A DNA vaccine is a vaccine that uses recombinant technology to clone target genes into eukaryotic expression vectors and introduce them into the body to express the corresponding antigens and induce a protective immune response for prevention and treatment. Existing DNA-based antigen delivery platforms include bacterial plasmids, recombinant viral vectors and bacterial vectors. While conventional influenza vaccines tend to induce organism-dependent immunity and lack T-cell immunity, DNA vaccines developed with conserved epitopes of influenza virus internal proteins tend to induce T-cell responses and play an important role in inhibiting virus transmission and clearing infected cells, facilitating broader cross-protection. Moreover, recombinant DNA molecules can encode multiple target gene fragments at the same time and highly express the target protein at the cellular level, which cannot only reduce the production cost of vaccines to a certain extent but can also stimulate both humoral and cellular immune responses. However, the immunogenicity and protective potency of DNA vaccines are low, which requires the design of optimized antigenic sequences or exogenous modifications to ameliorate them. For example, Guilfoyle et al. designed a polyvalent influenza DNA vaccine encoding HA and NA from H1N1 (2009) and H3N2 1968) strains and NP, M1 and M2 from the H1N1 (1918) strain. Immunization of ferrets with this DNA vaccine not only protected them from homologous attack by H1N1 pdm09 but also from the heterologous influenza virus H5N1, demonstrating the efficacy of this DNA vaccine against heterologous viruses . Using M8 strainsmRNA vaccines are produced by introducing mRNA containing encoded antigenic proteins into the body, which are transcribed and translated to produce the corresponding antigenic proteins and induce a specific immune response . For exaSubunit vaccines are further purified antigenic components based on cleaved virus vaccines, which have a higher safety profile but are less immunogenic. Improvement of immunogenicity is often achieved by adding suitable adjuvants, fusing multiple viral proteins and changing the vaccination strategy. For example, Saleh et al., evaluated the immunogenicity and protective properties of an influenza A virus H1N1 chimeric subunit vaccine (3M2e-HA2-NP) in a mouse model and found that mice vaccinated with this chimeric subunit vaccine produced specific antibody responses and stimulated cytokines for the production of memory CD4 cells and Th1 and Th2 cells, showing 75% protection against lethal attack by influenza virus . By fusiOverall, among the above vaccine development strategies, mRNA vaccines are the most promising for the following reasons: First, mRNA vaccines have a short development cycle and can be rapidly developed based on the genetic sequence of the virus. Second, mRNA vaccines are a dual mechanism of action for humoral and T-cell immunity. While conventional vaccines in the past focused on the induction of humoral immunity, mRNA vaccines produce both humoral and cellular immunity, stimulating T cells to prevent virus invasion and proliferation. Third, mRNA vaccines are immunogenic and do not require the adjuvant effect, avoiding possible immune side effects caused by adjuvants. Fourthly, mRNA vaccines do not carry viral components, have no risk of infection and are degraded through normal cellular processes, making them safe. As a final point, the mRNA vaccine technology has a simple production process, is easy to mass produce, and supports the goal of global supply ,110.Influenza continues to pose a significant threat to public health, and vaccination is currently the most effective measure to combat it. Although there are currently several manufacturers of influenza vaccines in China, the product composition is homogeneous and mainly consists of lysis vaccines, which are produced in chicken embryos. In addition to the long production time, another disadvantage is that adaptive mutations may develop and thus alter the protective effect of influenza vaccines. MDCK cell-based influenza vaccines could prevent this problem although these cell line-based vaccines are currently in their infancy in China. In addition, vaccination rates in China are low compared to those in developed countries. Many factors influence vaccination rates, including vaccination policies, vaccination history and knowledge and attitudes toward influenza and vaccination. To address these factors, measures need to be proposed to improve vaccination coverage.In addition, considering the ongoing global COVID-19 pandemic, occurrence of another influenza epidemic will generate a large number of cases with similar respiratory infection symptoms, thus increasing the complexity of the COVID-19 differential diagnosis. This can lead to the possibility that some COVID-19 cases may be difficult to detect and manage in a timely manner, which may exacerbate the risk of transmission of SARS-CoV-2 and bring about more serious health effects.To better control seasonal influenza and possible future influenza pandemics, it is urgent to design and develop a universal influenza vaccine that can address all types and subtypes of influenza viruses and produce durable immunity. In recent years, many important advances have been made in the development of a universal influenza vaccine, and several broad-spectrum influenza vaccines based on different targets and forms have been successfully validated in animal models. Some vaccine candidates have entered the clinical phase and have demonstrated good immunogenicity and safety, but no universal influenza vaccine has been approved for marketing, which may be related to the diversity and continuous variation of influenza virus types and the ultimate efficacy of the vaccine. This may impact sustained protection, as well as the issues of quality monitoring, market regulation and relevant policies.


Recent studies on the development of advanced targeted drug delivery systems using the dynamic behaviors such as specific surface protein affinity, morphological changes, and phenotypic polarization of natural cells are summarized. In addition to drug delivery mediated by dynamic behavior, functional “delivery” based on the natural cell themselves is also involved. Aiming to make the best use of the functions of cells, providing clues for the development of advanced drug delivery platforms.Digestive system cancer is the most common cause of cancer death in the world. Although cancer treatment options are increasingly diversified, the mortality rate of malignant cancer of the digestive system remains high. Therefore, it is necessary to explore effective cancer treatment methods. Recently, biomimetic nanoparticle delivery systems based on natural cells that organically integrate the low immunogenicity, high biocompatibility, cancer targeting, and controllable, versatile functionality of smart nanocarrier design with natural cells have been expected to break through the bottleneck of tumor targeted therapy. In this review, we focus on the dynamic changes and complex cellular communications that occur  Digestive system tumors mainly include esophageal cancer, gastric cancer, colorectal cancer (CRC), pancreatic cancer, hepatocellular carcinoma (HCC) and biliary tract cancer, and are the most common cause of cancer death worldwide. Its morbidity and mortality are in the forefront of malignant tumors Through decades of research, nanotechnology has shown great potential in diagnosing and treating various diseases in vivoAdditionally, the cell surface has specific signaling molecules, which can drive to the disease site, and can also dynamically alter its own morphology, secretion capacity or polarization state according to endogenous or exogenous factors Figure 1): morphological deformation of erythrocytes and neutrophils, vesicle secretion, macrophage polarization, and semi-biological hybrid cells, to promote further progress in this field.Here, we review dynamic drug delivery systems which use cells with transformable behavior instead of conventional nano- or cellular carriers. In this review, four categories of dynamic carriers of cells are covered according to their transformation behavior  of blood cells, and then lead to anemia, fever, infection, bleeding and vascular embolism and other clinical symptoms, and seriously affect the communication of information and material transfer between cells in vivo.The red blood cells (RBCs) in our bodies circulate for a long time, lasting about 100 to 120 days 2, which can be used as a good drug loading platform, and the conjugation of drugs onto the RBCs membrane can reduce the damage to the structure and function of RBCs to some extent et al. found that the cell activity of biotin acylation by biotin N-hydro⁃succinimide ester (NHS biotin) is the best, the recovery rate of RBCs can reach more than 90%, about 1000 biotins are connected to each RBCs membrane, and the activity is not affected for 24 hours in vivo3) cross-links into clusters on the membrane of senescent or degenerated RBCs, promotes the connection of IgG, and is more easily phagocytosed by macrophages. Therefore, RBCs carriers treated with Band3 cross-linking reagent have macrophage targeting properties. Lotero et al. treated RBCs carriers carrying etoposide with bis(sulfosuccinimidyl)suberate (BS3) and in vitro results showed that macrophage phagocytosis increased from 3% to 11%. The in vivo results showed that the treated RBCs carriers were liver-targeted due to the strong attachment of the Band3 to macrophages The surface area of a single RBC membrane reaches 160 μmet al. developed a “red blood cell hitchhiking (RH)” technology, which adsorbs drug loaded NPs onto RBCs and then infuses them to patients through intravenous injection or arterial intubation . After entering the blood circulation, the NPs are desorbed from the RBCs membrane under the influence of blood flow shear stress or in direct contact with endothelial cells . The results show that RH can deliver NPs to various types of cells on the surface of capillary lumen, and the type of cells to which NPs are delivered depends on the pathophysiological environment. This new drug delivery technology can accurately deliver nano drug carriers to selected organs by placing intravascular catheters in animal or human lungs, while avoiding RBCs hemolysis or toxicity to target organs, and has good biocompatibility In addition to using cross-linking agent to couple drugs to RBCs membrane, adsorbing drugs to RBCs membrane is also an effective drug loading strategy. Brenner et al. developed strategies to generate cellular and humoral immune responses against antigens. Researchers designed a RBCs hitchhiking system to mainly deliver the attached NPs to the spleen but not the lungs, thereby activating cellular immunity and humoral immunity, and they termed this process as erythrocyte-driven immune targeting (EDIT). Specifically, the researchers coat surfaces of polystyrene carboxylate (PS-COOH) with ovalbumin (OVA) as a model antigen using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) chemistry to generate protein-capped NPs attached to RBCs. Dendritic cells found all particles to be monodisperse and easily internalized and activated by them. As mentioned earlier, particulate matter can be removed from the lungs with RH technology because shear stress is experienced by RBCs undergoing deformation in the lung capillaries. Increasing the NPs to RBCs dosing ratio helps to improve the shear resistance in the lungs, thus allowing more NPs to be targeted to the spleen or other sites In addition to oxygen transport, RBCs have a variety of additional immunological related functions. Researchers have found that RBCs can bring immune complexes and bacteria from the circulatory system to liver macrophages and professional antigen presenting cells (APCs) in the spleen by capturing them on their surface. Through exploiting RBC's unique ability to present antigens in the spleen, Anvay Ukidve ex vivo loading and reinfusion of RBCs, or infusion of donor RBCs, each of which can have an impact on the final yield. The adhesion of NPs to RBCs is the basis of the RH strategy, but due to the small surface area to volume ratio of RBCs, there is also the problem that the drug loading is difficult to increase Despite improving the targeting and safety of drug delivery, RH strategy still has some problems: 1) NPs are not firmly connected to RBCs and easy to undergo desorption. 2) At present, the use of RH strategy to achieve the targeting of organs such as heart and brain requires the aid of arterial vascular cannulation, which is not suitable for chronic, outpatient treatment of diseases Neutrophils account for about 50% ~ 70% of the total number of leukocytes and are the most abundant leukocytes in human body in vitro. However, in practical applications, due to the short lifespan (~ 7 h) of neutrophils, intracellular degradation of drugs, insufficient number of obtained cells, and the potential for in vitro contamination, these methods are not effective in situ . Although this approach is more beneficial to clinical practice, it is crucial that NPs are designed to have high affinity for neutrophils. Li et al. constructed a strategy based on pathogen mimicking nano-pathogenoids (NPNs) to “hitchhiking” circulating neutrophils, and combined photothermal therapy to enhance the recruitment of neutrophils by NPNs from the blood circulation and the ability to eliminate residual tumor cells E. coli on NPs by extrusion method. During photothermal therapy (PTT), the chemokines produced stimulate the neutrophils and inform them of the tumor's location. Pathogen-associated molecular patterns (PAMPs) on NPNs are sensed and recognized by pattern recognition receptors (PRR) on neutrophils to “hitchhiking” circulating neutrophils, on the basis of which biological barriers are overcome and actively accumulate at the tumor site. After NPNs enter tumor tissue, in the process of forming neutrophil extracellular traps (NETs), NPNs are released from neutrophils when plasma membranes are destroyed and internalized by tumor cells to exert anti-tumor effect . Real-time intravital microscopy was used to examine the migration patterns of neutrophils in PTT-treated tumors, thus confirming that chemotaxis of neutrophils to tumors can overcome certain biological drug delivery barriers. Within 2 hours after PTT, a large number of neutrophils aggregated into tumors. In enlarged region I, the shape of neutrophils changed from oval to irregular as it moved slowly along blood vessels, sometimes adhering to vessel walls. In enlarged region II, when neutrophils are elongated, they can move more freely in small capillaries, allowing them to be evenly distributed throughout the tissue. In addition, neutrophils on blood vessels also enter the interstitium by elongating and squeezed through endothelial cells. The above results all indicated that the recruited neutrophils could cross the vascular barrier in a dynamic deformation manner and increase the distribution in the tumor tissue interstitium. The researchers further induced an inflammatory environment with PMA medium and verified that the encapsulated drugs could be released from neutrophils. The mechanism of its release lies in the dynamic deformation of activated neutrophils and eventually form NETs, which indicates the plasma membrane of neutrophils has disintegrated, thereby leading to the final release of the drug. Further results from in vivo experiments confirmed that PTT-induced inflammation led to the release of encapsulated NPs by NETs, followed by its eventual endocytosis by tumor cells. Usually, as a result of the limited penetration of light through tumor tissue, the uneven distribution of heat simply retards tumor growth but does not eliminate it completely, the result was a recurrence and metastasis of the tumor. By combining PTT and chemotherapeutic drugs, NPNs dislodge circulating tumor inducing neutrophils in situ, thereby eradicating tumors in all treated mice. This method also provides new ideas for improving nanomedicine delivery and tumor therapy The use of neutrophils to deliver drugs or NPs generally takes two forms. The first is to assemble NPs into neutrophils in vitro, and encapsulating nanoparticles with stem cell membrane can endow the nanocarrier with active targeting property, which can specifically accumulate in the tumor site, reduce the damage to the body's normal tissues and improve the therapeutic efficacy.Stem cells are a type of pluripotent cells with self-replication ability. Studies have shown that cytokines and chemokines secreted by tumor cells can induce the enrichment of stem cells into tumor tissue et al. constructed a MSCs membrane encapsulated DOX superparamagnetic iron oxide (SPIO) NPs for colorectal cancer treatment. DOX-SPIO@MSCs with the biological function of MSCs membrane, thus achieving highly efficient delivery of intracellular drugs, prolonging serum half-life, and actively targeting to the tumor site. Compared with free DOX and DOX-SPIO, DOX-SPIO@MSCs can not only avoid the premature clearance of drugs by the mononuclear phagocyte system, but also have stronger targeting to the MC38 xenograft tumor. The anti-tumor treatment efficiency was significantly improved without obvious systemic toxicity et al. noted that PLGA NPs encapsulated by umbilical cord derived MSCs could enhance the uptake of DOX, and the results showed that the uptake efficiency of membrane coated NPs by tumor cells was 3 times higher than that of membrane uncoated NPs. Moreover, encapsulation of umbilical cord derived MSCs improved the release efficiency of DOX at acidic microenvironment and inhibited MHCC97H subcutaneously tumor growth in nude mice with liver cancer To reduce the systemic toxicity of doxorubicin (DOX), Liu et al. found that RBCs release EVs from their surface in vivo, research on EVs and drug delivery has increased gradually in the recent years Table 1. In addition, EVs have lipid bilayers, so lipid-soluble molecules can be anchored and inserted into the membrane. Combined with cell membrane surface modification technology, functionalized EVs can be obtained, which further expands the application of EVs as drug carrier Under physiological and pathological conditions, almost all kinds of microorganisms or mammalian cells will dynamically release extracellular vesicles (EVs). EVs are diverse membranous vesicles derived from endosomes and cell membranes released by cells into the extracellular environment in vitro culture, so as to generate EVs with stable characteristics, which can be used as drug carriers for the development of new cancer therapeutic drugs. Macrophage derived EVs can penetrate the blood-brain barrier, interact with and accumulate in cancer cells EVs is a highly heterogeneous vesicle et al. constructed a hybrid carrier consisting of macrophage derived EVs encapsulating different therapeutic agents and iron oxide NPs to achieve spatial control of drug delivery. Studies have found that under a magnetic field, the uptake of EVs by tumor cells can be dynamically regulated and spatially controlled, and that magnetic targeting enhances tumor cell death with attenuated toxic side effects Inspired by EVs mediated intercellular communication, Silva et al. modified exosomes with cationic amylopectin to target asialoglycoprotein receptors on hepatocytes et al. treated parental cells with azide membrane-fused liposomes (MFL) to create azide exosomes that were then conjugated with a tumor targeting peptide conjugate DBCO-CGKPK via bioorthogonal reaction Figure 4).With endogenous exosomes, immune reactions can be avoided. Nevertheless, the efficiency of exosome delivery depends on both the parent and the recipient cells, and native exosomes have difficulties locating their target cells in vitro and in vivo experiments et al. found that after oral administration of ginger derived EVs in mice, they mainly accumulated in the liver and mesenteric lymph nodes, and could inhibit ROS production when acting on hepatocytes The majority of studies at present focus on EVs derived from animal cells. However, the production efficiency of EVs derived from animal cells is low, and only a few micrograms can be obtained in billions of cells Figure ). After treatment with GDNs, the severity and pathological score of colitis in mice decreased . The expression of E-cadherin, IL-6 and IL-1β in colon epithelial cells were significantly reduced . The mRNA levels of chemokines MCP-1, CXCL9 and CXCL10 were also reduced , and the inflammatory neutrophil infiltration of CD11b+Ly6Chigh was significantly reduced , suggesting that GDNs could enhance the anti-inflammatory capacity of intestinal immune cells by playing the role of immune regulators PDENs have been successfully reported for oral colon-targeted drug delivery Outer membrane vesicles (OMVs) are a type of membrane-shaped structure originated from the bacteria's outer membrane and mainly produced by Gram negative bacteria et al. by adding polyethylene glycol (PEG) and the Arg-Gly-Asp (RGD) peptide to increase blood circulation and improve tumor targeting. On top of the tegafur-loaded NPs, modified OMVs were coated, and the resulting NPs had three antitumor functions . As a first step following systemic injection, innate immune cells are activated, followed by an enhanced tumor accumulation in response to the EPR effect and peptide targeting by RGD. After being taken up by tumor cells, OMVs dynamically released tegafur, which enhanced the sensitivity of cancer cells to cytotoxic CD8+ T cells and eliminated myeloid-derived suppressor cells (MDSCs), thereby synergistically enhancing the immunotherapy ability of OMVs In order to relieve the state of tumor immunosuppression, combining the anti-tumor immune response mediated by OMVs with chemotherapeutic drugs is a more effective approach. By combining immunotherapy and OMVs, additional potential for tumor immunotherapy can be enhanced to prevent tumor recurrence and metastasis and complete eradication of tumors. The detoxified OMVs were modified by Ping  Staphylococcus aureus (S. aureus) mutants by genetic engineering that produce avirulent cytolysins, and OMVs containing avirulent cytolysins that are immunogenic and nontoxic are able to protect mice against S. aureus et al. used genetic engineering to modify the parental Escherichia coli (E.coli) to reduce the cytotoxicity of OMVs, expressed the tumor targeting ligand HER2 on their surface, and loaded siRNA to inhibit the activity of overexpressed spindle kinesin within tumor cells. Consequently, cell proliferation is inhibited and apoptosis is induced. The experiments showed that AffiHER2OMVsiRNA was not significantly cytotoxic and could aggregate at the tumor site with high specificity, effectively inhibiting tumor growth The safety of using OMVs for cancer treatment is a major concern. Although many studies have demonstrated that the use of attenuated or detoxified OMVs as drug delivery carriers are safe in mice Megakaryocytes produce small, anucleate cells called platelets, whose lifespan is about 8 ~ 10 d, and their main function is hemostasis, regulating inflammation, and promoting thrombosis In vivo studies have shown that platelet microparticles can promote the growth of primary tumors, stimulate vascularization, and promote the formation of distant metastases Studies have shown that platelets are involved in tumor development, including tumor growth, tumor cell extravasation, and metastasis, by protecting tumor cells from the host immune system, whereas platelet effects on local and distant tumor host interactions may be mediated through the secretion of large amounts of platelet microparticles and exosomes et al. created platelet-mimicking nanovehicles (PM-NV) in vivo experiments, PM-NV was found to contain a large amount of platelet-derived “self-recognition” proteins, which minimizes in vivo immunogenicity and prolongs circulation time. CD44 molecules are present on tumor cell membranes and can be bound by P-selectin carried on platelet membranes. This allows TRAIL-DOX-PM-NV to target tumor cells and accumulate at the tumor site. Meanwhile, TRAIL-DOX-PM-NV aggregation on tumor cell surfaces encourages TRAIL interaction with the membrane and signals exogenous apoptosis. More importantly, when TRAIL-DOX-PM-NV was internalized by cells, the acidic environment of lysosomes would mediate TRAIL-DOX-PM-NV to dynamically release DOX, allowing DOX to accumulate in tumor cell nuclei and synergistically induce tumor cell apoptosis . In addition, the binding of P-selectin to CD44 can eliminate CTCs, preventing tumor metastasis. Based on platelet and tumor cell specific affinity, this study successfully developed platelet membrane modified nanomedicines that delivered TRAIL and DOX to tumor cells.A great deal of attention has been paid in recent years to the interactions between platelets and CTCs in the blood et al. Primary amine or thiol residues on the surface of platelets enable chemical attachment to NPs or biomolecules, followed by dynamic release of drug loaded microparticles via activation The body's immune system functions as an immune surveillance that can recognize and clear mutant cells from the body et al. et al. designed a protein that can specifically bind to SIRP-α and inhibit the colony stimulating factor-1 receptor (CSF-1R) through computational biology. The supramolecules can self-assemble with specific compounds into nanoparticles. After targeting macrophages, the supramolecules can block the mutual binding of macrophage SIRP-α receptors and CD47, and block the CSF-1R signaling pathway, so that TAMs are polarized to the M1 type and induce an innate immune response against tumors Peptides targeting M2 macrophages can be used to modify carriers capable of delivering drugs that promote macrophage transformation to achieve TAMs-specific regulation. Signal transducer and activator of transcription 6 (STAT6) and nuclear factor kappa-B (NF-κB) promote M2 polarization of macrophages through different mechanisms. Therefore, inhibition of these two signaling pathways may lead to a phenotypic transformation in macrophages. Xiao Figure 8). For a long time, iron oxide nanoparticles have been used for imaging liver tumors due to the trait of specific aggregation in liver tissue, a property that highlights their advantages for liver tumor therapy et al. used hyaluronic acid (HA) encapsulated superparamagnetic iron oxide nanoparticles (IONs) to construct reprogrammed macrophages (HION@Macs). In vitro and in vivo studies demonstrated that HION@Macs were able to educate in situ M2 macrophages toward M1 transition and restore their immune effects via a paracrine manner. HION@Macs also exhibits strong resistance to the immunosuppressive tumor environment, enabling sustained production of inflammatory factors  to inhibit the growth of cancer cells and promote their apoptosis, exerting a synergistic tumor suppressive effect Several classes of microbial agents and microbe derived molecules  were shown to drive the antitumor cytotoxic effects of macrophages, related clinical research has also been carried out, but their clinical efficacy has been modest in vivo, this strategy is still very far from clinical translation. Because in most cases, M1 type macrophages induced to undergo polarization by in vitro stimulation readily revert to the M2 phenotype after reaching the tumor immune microenvironment in vivo. Based on this purpose, a cellular “backpack” strategy that can maintain the duration of M1type polarization of macrophages has emerged. Several drug delivery demonstrations using the “backpack” strategy have been carried out over the past few years Although there have been many studies that successfully induced phenotypic transformation of macrophages et al. integrated interferon gamma (IFN-γ) into a “backpack”, and IFN-γ as a pro-inflammatory macrophage stimulator can sustain macrophages in a tumor-killing M1 type state. In mice with cancer, the maintenance effect slowed tumor growth and reduced metastasis for up to five days. Specifically, the team fabricated two layers of the biocompatible polymer poly  sandwiched with polyvinyl alcohol (PVA) and the cytokine IFN-γ. To complete the “backpack”, a layer of cellular adhesive was also added to help the “backpack” fit snugly on the macrophages. In addition, they attach easily and do not become phagocytosed or digested by macrophages due to their disc-shape, allowing them to survive for longer periods of time. The researchers injected “backpack”-carrying M1 macrophages into the tumors of mice and assessed them seven days later. Based on the findings of the in vivo study, macrophages carrying an IFN-γ “backpack” exhibited M1 indicators for more than 48 hours. As compared to cells injected with free IFN-γ or cells with a blank “backpack”, there was a significant difference in expression level of M1 indicators. Additionally, treatment with IFN-γ “backpack” therapy resulted in fewer metastatic nodules, smaller tumors, and longer lifespans than control group. Interestingly, not only do “backpack” -wearing macrophages stay in the M1 state, but it can also repolarize other macrophages including TAMs towards the M1 phenotype in vivo. In contrast to other studies, this effect was achieved at 100 times less than the maximum total dose of IFN-γ, and the mice did not show any signs of treatment toxicity Wyatt Shields IV As a result of the “backpack” strategy, macrophages adoptively transferred into solid tumors will retain their phenotype in an immunosuppressive environment. To improve its efficacy against solid tumors, future research can continue to delve into the optimal way of packing the stimulator into the “backpack” and its release kinetics. In addition, “backpack” can be combined with adjunctive therapies to increase the therapeutic effect. These strategies should also not be restricted to macrophages and can also engage other circulating cells with increased chemotactic sensitivity to mount a more robust tumor immune response Abundant chemical groups on cell membranes are able to create interactions with the interfaces of nanomaterials or carriers. Based on this, coupling synthetic materials to the cell surface or encapsulating nano-drugs inside the cells can promote the exposure of tumor-associated antigens and induce tumor immune responses on the one hand, on the other hand can realize multimodal therapy of tumors by combining PDT or PTT, and most importantly, the constructed biomimetic nanocarriers have the property of actively targeting tumor sites. Such biomimetic nano-drug delivery systems constructed or modified artificially we call them semi-biological hybrid cellular transformers. By active targeting effect, it can reduce the non-specific distribution of drugs in the body, and the safety and efficacy of treatment can be improved In addition to artificially modified ligands, certain specific types of cells have been regarded as potential drug delivery vehicles due to their abilities to homing to tumors and long circulation in the blood. For example, tumor cell membranes can be exploited for surface functionalization of nanoparticles, thereby endowing them with the ability for homologous targeting to achieve tumor specific drug delivery Although semi-biological hybrid cellular transformers can also be surface modified or loaded with drugs, there are some differences with EVs drug delivery systems. The difference between the two is that EVs, as part of the cell, only inherit some of the cell's properties. In order to develop dynamic drug delivery systems using EVs, it is usually necessary to introduce functional components into cells and release them in the form of EVs when the parent cells are exposed to specific stimuli Loss of tumor antigen expression is one of the important mechanisms of immune escape. Tumor cells evade killing by the immune system by downregulating the expression of strong rejection antigens, downregulating major histocompatibility antigen I (MHC-I) levels, and impairing antigen-presenting function et al. coated sulfasalazine (SAS) - loaded magnetic iron oxide nanoparticles (Fe3O4 NP) with platelet membrane by extrusion method to obtain biomimetic nanoparticles Fe3O4- SAS@PLT with better stability. P-selectin on the surface of platelets works in conjunction with CD44 on the surface of 4T1 tumor cells to increase the uptake of nanoparticles and promote the accumulation of nanoparticles in metastatic tumors. The ingested magnetic iron oxide and sulfasalazine synergistically induce ferroptosis, expose TAAs, and activate antitumor immune responses . The rate of DC maturation induced by biomimetic nanocarriers was increased to 69.9%, which was significantly higher than that of nanoparticles without platelet membrane coating (28.4%). Programmed death (PD-1) inhibitors and this biomimetic nanocarrier were combined to treat tumor bearing mice, achieving 76% of mice survival up to 80 days, while the mice in other control groups all died within 50 days Recently, a new form of cell death known as ferroptosis has been discovered that could improve immunogenicity of tumors. The existing agents that induce tumor cells to undergo ferroptosis usually face two major problems of being easily cleared by the body's immune system and being difficult to target. Jiang et al. reported an activated AF coated semiconductor polymer nanoparticle (SPN) for enhanced tumor phototherapy There are many tumors stromal cells in the TME, including cancer-associated fibroblasts (AF), and this occupies a major position as a barrier to the development of cancer treatments. On the one hand, AF secretes many growth factors and cytokines to activate tumor related signaling pathways to promote angiogenesis, tumorigenesis, progression, metastasis, and resistance generation 3) were embedded into T cell membranes by glycometabolism technology, and then the extracted N3 functionalized T cell membranes were encapsulated on the surface of indocyanine green (ICG) - loaded polymeric nanocores to construct biomimetic nanoparticles (N3⁃TINPs). A special protein  on the T-cell membrane endowed N3⁃TINPs with immune recognition ability to tumor cells, while functionalized N3 groups enabled efficient and specific bioorthogonal reaction with BCN groups of artificial targets for glycometabolic labeling on tumor cells . N3⁃TINPs greatly enhance the enrichment of ICG at the tumor site to effectively overcome the tumor “off target effect”, thus improving the antitumor efficacy of nanocarriers based on their tumor targeting with immunomodulatory drugs using artificial targeting and natural target based dual guide therapy Recently, as a representative of adoptive cell therapy, CAR-T has achieved a large breakthrough in the treatment of hematological tumors. But due to the limitation of many factors, such as the lack of tumor specific antigen and the suppressive tumor immune microenvironment, CAR-T therapy still faces a great challenge in the treatment of solid tumors +T cells by metabolic labeling and click chemistry, giving them stronger tumor targeting and killing In recent years, aptamers as novel targeting ligands can also modulate the body's antitumor immune response by binding immune related receptors, which could be applied to tumor immunotherapy. In 2019, an osteosclerotic protein aptamer drug developed by the research team of Hong Kong Baptist University has been granted orphan drug certification by FDA for the treatment of osteogenesis imperfecta et al. constructed an angiopep2 modified biomimetic nanocarrier of RBCs membrane loaded with polymer coloaded DOX and lexiscan (Lex). Lex can transiently open the BBB and increase the permeability of the nanomedicine to the brain, while angiopep2 can target the highly expressed LRP in the GBM, promoting the passage of the nanomedicine through BBB and achieving GBM targeting while prolonging the circulation time of the NPs et al. constructed ApoE peptide modified RBCs membrane encapsulated temozolomide (TMZ) and the epigenetic bromodomain inhibitor (OTX015) biomimetic nanocarriers to achieve synergistic chemotherapy and immune therapy for GL261 GBM. In contrast to previous studies, ApoE peptides can target multiple overexpressed low-density lipoprotein family receptors (LDLRs)  in BBB endothelial cells and GBM cells, thus providing superior BBB penetration and tumor targeting capabilities  + and CD8 + T cells through induction of immunogenic cell death and suppression of PD-1/PD-L1 coupling Since tumor surface markers are different, the selection of suitable cell membrane surface modifiers is crucial for the targeting of biomimetic nanocarriers. Low density lipoprotein receptor related protein (LRP) receptors are overexpressed in endothelial cells of the BBB and in U87MG GBM cells. Based on this property, Shi 2O2 content, and overexpression of glutathione, while a cascade bioreactor constructed by combining natural cell membranes with nanomedicines is able to modulate the tumor microenvironment, improve radiotherapy, and support immunotherapy.Currently, although surgery, chemotherapy, and radiotherapy are all effective methods of suppressing primary tumors, nearly 90% of cancer-related deaths are still caused by cancer cell metastasis et al. used Ti₃C₂ nanosheets as carriers to chemically conjugated with glucose oxidase (GOX) and chloroperoxidase (CPO) and load deoxygenation-activated prodrug tirapazamine (TPZ) to prepare a cascaded-enzyme nanoreactor Ti₃C₂- GOX - CPO / TPZ (TGCT), which was finally encapsulated into tumor cell membrane carriers with high expression of CD47 (mₑTGCT). Because the encapsulation of highly expressed CD47 biomimetic membrane, mₑTGCT exhibits superior immune escape ability as well as homologous targeting ability, which can be preferentially targeted to tumor sites and effectively enhanced tumor cell uptake. After entering tumor cells, GOX and CPO can produce a large amount of HClO through a cascade reaction, achieving highly efficient enzyme dynamic therapy (EDT). In addition, A further laser irradiation can increase singlet oxygen (¹O₂) production by accelerating enzyme catalyzed reactions. Meanwhile, the oxygen consumption of phototherapy and EDT could aggravate the hypoxic state inside the tumor, and then activate the deoxygenation-activated prodrug TPZ to realize chemotherapy. Experimental results showed that mₑTGCT can effectively inhibit tumor growth because of the amplified synergistic therapeutic effect of tumor phototherapy, enzyme dynamic therapy, and chemotherapy . A cascaded enzyme nanoreactor proves to be a promising way of achieving synchronized and remarkable antitumor therapy et al. created a bacterium, Escherichia coli (MG1655), that overexpresses the NDH-2 enzyme (respiratory chain enzyme II) and colonizes tumors and increase the generation of H2O2. Subsequently, the experiments covalently linked magnetic Fe3O4 nanoparticles with bacteria and acted as a catalyst for Fenton-like reaction to transform H2O2 into toxic hydroxyl radical (•OH) for tumor therapy. The structures proved that the constructed bioreactor sustainably produced H2O2 with engineered bacteria for performing Fenton-like reaction, while the generated toxic •OH could effectively induce tumor cell apoptosis. With this bioreactor, it is possible to achieve aggressive tumor colonization as well as self-sufficient Fenton-like reactions without the need for additional H2O2Liu Table 2). The promotion effects of biomimetic nano-drug delivery systems for digestive system tumor therapy are mainly reflected in the following aspects. 1) The optimal multi-drug co-delivery system can be designed according to the inherent characteristics of various cell membranes, and the mixing ratio of cell membrane and nanoparticles can be adjusted to optimize the fusion process and achieve higher encapsulation efficiency and good controlled release capability. 2) Precise modification of nanocarriers can be achieved by recognition, removal or addition manipulation of specific antigenic proteins on the cell membrane surface to improve the tumor targeting ability. 3) By modifying nanocarriers with hybrid membranes, or incorporating ligands consisting of antibodies, nucleic acids or enzymes into the cell membrane for surface functionalization, a variety of biological functions beyond the single cell membrane are introduced to enhance the synergistic effect in tumor immunotherapy. 4) Cell membrane modified nanocarriers prepared from patients' own cells can be utilized for individualized drug delivery and treatment to achieve the effect of precision treatment of tumors. 5) It can promote the extensive combination of chemotherapy, radiotherapy, photothermal therapy and other treatment methods, and realize the integration of various tumor treatment methods.Worldwide, digestive system cancer is still the leading cause of cancer death. Digestive system cancer is still the most common cause of cancer death worldwide. The clinical treatments for digestive system tumors are still conventional surgery, chemotherapy and radiotherapy. Surgical treatment, which is more effective for early-stage tumors that have not spread, but with the development and metastasis of malignant tumors, the curative effect and prognosis of advanced tumors are poor, and often cannot completely clear all cancer cells in the human body. Although chemotherapy can play a certain role, due to its lack of specificity, there is a large damage to the normal cells and immune system of the body, and it is easy to increase the body's drug resistance and cause adverse reactions. Radiotherapy has the problem of long cycle length and significant toxic side effects to human body. Some novel therapies such as immune checkpoint inhibitors, targeted agents, and CAR-T have played an important role in the treatment of digestive system cancer, but they also suffer from defects such as drug resistance and severe adverse effects. Under this background, the new idea of biomimetic nano-drug delivery system based on natural cells may change the situation of digestive system malignant tumor treatment  into nanocarriers treatment offers a wider range of possibilities.Nonetheless, research on natural cell-based biomimetic nanoparticle drug delivery platforms in the diagnosis and treatment of digestive system tumors is still in its infancy, and many challenges need to be overcome for the transition from experimental research to clinical applications. One of the most important points is how to guarantee the safety of biomimetic NPs. Current production technologies of biomimetic NPs are not mature enough, and the resulting complex and varied production processes, inconsistent standards and poor reproducibility will affect the efficacy and safety of the final products; Second, existing characterization methods are limited, and the success of membrane coating is verified only by particle size detection and morphological observation. Western blot analysis can only demonstrate whether the surface composition of biomimetic nanocarriers is similar to that of the source cell membrane, but cannot verify whether the membrane is partially disrupted after membrane coating and whether biochemical reactions occur during the coating process or introduce unknown components that pose a hidden danger to drug safety. Moreover, biomimetic NPs with improper storage are prone to denaturation of membrane proteins, resulting in potential immune responses to endogenous antigens, which in turn cause tissue damage to the body. Additionally, its safety issue should be well considered when using certain special cell membranes such as tumor cell membrane or bacterial membrane. Inappropriate immunogenic exposure may induce detrimental immune responses, even against normal cell types, and long-term safety should be considered. Overall, to further improve the safety and efficacy of biomimetic NPs, the problem of poor reproducibility and inconsistent standards in the preparation process should first be addressed. Besides, innovative methods and infrastructure for natural cell acquisition require optimization, along with high-quality storage of natural cells and efficient characterization methods. During the production preparation process, it is imperative for the surface markers and specific functions of natural cells to not be destroyed. Yet, this remains an urgent problem in the current natural cell biomimetic nanoparticle drug delivery system towards clinical application. In addition, the tumor permeability, systemic cumulative toxicity, self-degradability and body excretion pathway after targeting biomimetic nanoparticle drug delivery to the tumor site still need to be explored.Table 3). In conclusion, despite the great success of natural cell biomimetic nanoparticle drug delivery for treating tumors, this innovative strategy still stays at the laboratory stage and cannot meet the requirements for clinical applications because there are currently no suitable methods to ensure the controllability of the preparation process and the safety and efficacy of the use process. However, challenges always coexist with opportunities. From the laboratory to the clinic, there are still many issues that must be addressed urgently. But the unique advantages and application potential of the natural cell biomimetic nanoparticle drug delivery system are still undeniable, which provides the design and application of nano-drugs. The new thinking mode will have a place in the field of precision medicine.The ultimate goal of discovering and developing biomimetic nano-drug delivery system is to reach the clinical stage and achieve large-scale industrial production. Most of the studies on the drug-loaded biomimetic NPs are still in the preclinical stage. Some formulations have undergone clinical research and may be used to serve patients soon (


ALAS is evolutionarily related to transaminases and is therefore classified as a fold type I PLP-dependent enzyme. As an enzyme controlling the key committed and rate-determining step of a crucial biochemical pathway ALAS is ideally positioned to be subject to allosteric feedback inhibition. Extensive kinetic and mutational studies demonstrated that the overall enzyme reaction is limited by subtle conformational changes of a hairpin loop gating the active site. These findings, coupled with structural information, facilitated early prediction of allosteric regulation of activity via an extended C-terminal tail unique to eukaryotic forms of the enzyme. This prediction was subsequently supported by the discoveries that mutations in the extended C-terminus of the erythroid ALAS isoform (ALAS2) cause a metabolic disorder known as X-linked protoporphyria not by diminishing activity, but by enhancing it. Furthermore, kinetic, structural, and molecular modeling studies demonstrated that the extended C-terminal tail controls the catalytic rate by modulating conformational flexibility of the active site loop. However, the precise identity of any such molecule remains to be defined. Here we discuss the most plausible allosteric regulators of ALAS activity based on divergences in AlphaFold-predicted ALAS structures and suggest how the mystery of the mechanism whereby the extended C-terminus of mammalian ALASs allosterically controls the rate of porphyrin biosynthesis might be unraveled. PyridoxALAS1, which acts as a “housekeeping” gene and initiates heme biosynthesis in all cells for production of cytochromes and other heme-binding proteins, and ALAS2, which is expressed only in developing erythrocytes and produces, almost exclusively, the much larger quantities of heme required for hemoglobin formation , consensus sequences containing a cysteine-proline dipeptide with the cysteine functioning as a ligand to Fe3+-heme   HRMs 4 and/or 5 facilitate feedback inhibition of ALAS1; 2) under oxidizing conditions, the CXXC motif forms a disulfide bond that causes the C-terminal extension to fold over HRMs 4 and 5 such that it sterically prevents hemin binding and feedback inhibition; 3) under non-oxidizing conditions, the CXXC motif is reduced and adopts an alternative conformation wherein HRMs 4 and 5 are exposed to provide feedback inhibition by excess heme. Stated more concisely, feedback inhibition of ALAS1 by heme is dependent upon cellular redox status.Based on the alignment of the ALAS2 structures we put forth the following postulates: 1) the C-terminal extension of ALAS2 adopts two different conformations, neither of which prevents feedback regulation via heme binding to HRMs 4 and 5. 2) In ALAS2 oxidizing conditions cause disulfide bond formation in the CXXC motif and movement of the extended C-terminus not over HRMs 4&5 but instead to a more equatorial and activated position relative to the enzyme, thereby relieving the autoinhibition observed when the extended C-terminus folds over the active site. Stated more succinctly, heme and redox status independently regulate ALAS2 activity.These postulates are not incompatible with the possibility of protein-protein interactions regulating activity. Of course, experimental data will be required to further support or refine the views presented here, but whatever the outcome the remarkably divergent structures discussed here will likely represent a key test of the capacity of AlphaFold to discern fine structural differences and facilitate prediction of allostery in all enzymes, including those dependent upon PLP for functionality.


The 2022 European of Society of Cardiology (ESC) Guidelines on cardio-oncology, developed by the ESC Cardio-Oncology Task Force in collaboration with the European Hematology Association, the European Society for Therapeutic Radiology and Oncology, and the International Cardio-Oncology Society, represent an essential resource for health care providers, including not only cardiologists, cardio-oncologists, and primary care physicians, but also medical oncologists prescribing cancer therapeutics that may adversely impact cardiovascular health, and ultimately cancer survivorship.Although the 2022 ESC guidelines are uniquely comprehensive in scope and represent a major overhaul of prior ESC guidelines published in 2016,In order to exemplify the conundrum posed by having discordant expert-derived guidelines, we focus here on discordance between the 2022 ESC guidelines and 2016 ASCO guidelines for monitoring of patients receiving anti-HER2 therapy, as summarized in The primary value of cardiac surveillance, whether with TTE and/or cardiac biomarkers, is to not only to confirm symptomatic cardiac therapy–related cardiac dysfunction (CTRCD), the term used by the ESC panel, but perhaps more importantly detect asymptomatic CTRCD that may trigger interrupting or even withholding anti-HER2 therapy, and/or initiating cardioprotective therapy such as beta blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers. According to Table 25 of the ESC guidelines, anti-HER2 therapy should be interrupted if there is symptomatic moderate-to-severe CTRCD (as defined in Table 3), or asymptomatic CTCRD with left ventricular ejection fraction <40%. In addition, the guidelines recommend that anti-HER2 therapy be continued with guideline-directed medical therapy for asymptomatic CTRCD with a left ventricular ejection fraction of at least 40%. Although these criteria provide clear and valuable guidance regarding continuing anti-HER2 therapies in those with asymptomatic CTRCD, there remain 3 fundamental issues regarding universal screening in all cardiac risk groups and normal cardiac function at baseline for asymptomatic CTRCD.,First, the risk of CTRCD associated with anti-HER2 therapy, specifically monoclonal antibodies including trastuzumab or the trastuzumab/pertuzumab combination, is greatest when following anthracycline therapy, which are much less commonly used as adjuvant or neoadjuvant therapy for breast cancer given the comparable effectiveness of nonanthracycline regimens. For patients with a low baseline cardiovascular risk receiving nonanthracycline chemotherapy regimens, the likelihood in asymptomatic patients meeting any of the criteria for interrupting anti-HER2 therapy and/or initiating cardioprotective therapy by the 2022 ESC guidelines is very low for both localized and metastatic disease,Second, other commonly used HER2-targeted therapies such as anti-HER2 tyrosine kinase inhibitors  and antibody-drug conjugates  are also associated with very low CTRCD risk.Finally, the level of evidence supporting the specific ESC recommendations for cardiac monitoring during and in the first 12 months after HER2 therapy is low. For each guideline, the ESC panel provided a class of recommendation , and level of evidence supporting the guideline, including Level of Evidence: A , Level of Evidence: B , or Level of Evidence: C . Of the 9 recommendations applicable to cardiac surveillance in patients receiving anti-HER2 therapy, 7 are supported by consensus opinion and the lowest level of evidence (C), whereas a lower B level of evidence was cited as supporting 3 monthly cardiac surveillance using TTE. In fact, of the 156 Class 1 recommendations summarized at the end of the ESC guidelines, only 5 (3%) were supported by the highest level of evidence (Level of Evidence: A), whereas 118 (76%) were supported by expert consensus without robust data (Level of Evidence: C). This highlights the need to harvest and mine real-world data, develop prospective registries designed to address knowledge gaps, and develop traditional and pragmatic clinical trials, all of which will ultimately generate the evidence required to better inform and revise current guidelines. The ESC panel indeed recognized “gaps in the evidence”—we agree that substantial gaps exist and suggest that evaluation and validation of cardiac surveillance algorithms for the entire spectrum of anti-HER2 therapy be added as a knowledge gap and identified as a research priority. We also particularly emphasize the evidence gap and need for additional research regarding “optimal follow-up…after treatment for cancer,” especially after cardiotoxic anthracycline therapy, in which follow-up surveillance beyond 12 months after completing therapy is currently not recommended in the ESC guidelines, but risk of insidious and delayed CTRCD may be high.In conclusion, the 2022 ESC Guidelines on cardio-oncology represent an impressive and important effort for providing greater clarity in defining cardiotoxicities of emerging anticancer agents, minimizing the potential cardiovascular complications of myriad cancer therapies, and assuring healthy cancer survivorship. The authors of the guidelines and the organizations supporting their development need to be congratulated for their important efforts and encouraged to lead the charge in generating the evidence required to support and refine the current guidelines.This work was supported in part by grants from the Department of Health and Human Services and the National Institutes of Health, National Cancer Institute (P30CA196521). Dr Sparano has served as a paid consultant for AstraZeneca, Roche, and Seagen. Dr. Sahni has reported that she has no relationships relevant to the contents of this paper to disclose.


According to the hallmarks of cancer, typical processes of human cancer initiation, progression, and metastasis are essentially influenced by pathologic epigenetic deregulations via DNA methylation and/or histone modification ,2, leadiIn particular, modifications of histones—such as histone de-/acetylation—represent a central epigenetic regulatory mechanism which leads to relevant alterations of chromatin structure due to dysregulated noncovalent interactions within and between nucleosomes, and play a significant role in human carcinogenesis ,5. HistoRegarding our knowledge of the role of HDACs in human carcinogenesis, more than thirty years of developing HDAC inhibitors have passed since the first report of a potent zinc-dependent histone deacetylase . To date(i)Mayr et al. investigated the HDAC expression in biliary tract cancer (BTC) in relation to effects of HDAC inhibitors in-vitro (using established BTC cell lines) and to clinical endpoints in-situ (using BTC specimens). They could demonstrate that: (i) HDAC inhibition show a significant cytotoxic effect alone; and that (ii) especially the HDAC class I  inhibitor romidepsin could significantly augmented the cytotoxic effect of the standard chemotherapeutic cisplatin on the BTC cell lines. Furthermore, HDAC2 expression in human BTC specimen could be used as the diagnostic and prognostic biomarker. From this study, the conclusion could be that HDAC inhibition might be a promising combinatory drug approach in BTC as a cancer entity with dismal prognosis and that the tissue expression levels of HDACs seems to be an interesting biomarker in BTC [r in BTC .(ii)Maria Hernandez-Valladares et al. studied the in vivo proteomic/phosphoproteomic effects of all-trans retinoic acid (ATRA) and valproic acid (VP) on primary acute myeloid leukemia cells derived from patients before and during disease-stabilizing treatment. Prior to epigenetic therapy, the proteome and phosphoproteome profiling of the AML responders/non-responders cases revealed significant difference in processes of neutrophil degranulation/differentiation, M phase regulation and the interconversion of nucleotide di- and triphosphates , as well as RNA metabolism and apoptosis. Treatment of AML cell lines with the combination of ATRA and VP leads to proteomic and phosphoproteomic modulation of DNA strand elongation, RNA processing, actin/cytoskeleton and cholesterol metabolism as well as GTPase/intracellular signaling in relation to results from AML responders and non-responders. Therefore, the authors suggested that proteomic and phosphoproteomic profiling can be applied as a predictive “tool” for identification of responders to ATRA/VP-based treatment [reatment .(iii)Sanne Venneker et al. investigated the changes of the methylome from IDH-mutant enchondroma towards high-grade chondrosarcoma in situ and performed an epigenetics and combinatory compound screening in chondrosarcoma cell lines in vitro, too. They could show that: (i) methylation is increased with the grading of IDH-mutant chondroid-derived neoplasm; and (ii) that chondrosarcoma cell lines were sensitive to HDAC inhibition in 2D and 3D in vitro models independent to their IDH mutation status. Detailed analysis with drug screenings revealed specific pro-apoptotic effects of class 1 HDAC inhibition on chondrosarcoma cells leading to synergistic effects in the combination with Bcl-2 family member inhibitors. Therefore, the authors concluded that combination therapies of specific HDAC inhibitors and small molecule inhibitors could be a promising strategy to improve therapeutic efficacy in chondrosarcoma [osarcoma .(iv)Robert Jenke et al. provided an up-to-date, comprehensive, and very structured overview of recent status and ongoing developments of HDAC inhibitors in the field of anticancer therapy. They summarized the molecular mechanisms of HDACi-linked anticancer effects to “classically” induce apoptosis and autophagy as well as senescence, whereby new insights on DNA damage, hormone signaling, and immune regulation by HDACi are presented. Regarding therapeutic aspects, the authors of this review display how combinatory approaches of HDACi with phosphoinositide 3-kinase-EGFR inhibitors and hormone or immunotherapy could improve therapeutic efficacy. Finally, very interesting developments regarding new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs) are discussed in detail. Based on the pre-clinical and clinical results of bifunctional HDAC inhibitors, the authors postulate that the upcoming concept of polypharmacy with HDACs is very promising for the field of cancer therapy [ therapy .(v)Hélène Losson et al. focus in their review on the possible role of HDAC6 as a new and clinically relevant target in chronic myeloid leukemia (CML). First of all, the authors could definitively demonstrate the specific involvement of HDAC6 in human oncogenesis of human tumors via different mode of actions. Looking in detail at CML: (i) nuclear shuttling of HDAC6 with p53-HDAC6 interactions; (ii) the HDAC6 related acetylation status of HSP90 for degradation of BCR-ABL; and (iii) the overexpression of HDAC6 in CML stem cells make especially HDAC6 an interesting target in CML [t in CML .In what follows, we try to address some specific points and issues of the papers  published in this Special Issue to highlight the great potency to target deregulated HDACs in human cancer:https://clinicaltrials.gov, accessed on 12 August 2022) returned 188 hits overall  indicating the fact that HDAC inhibitors have now arrived in clinical research. However, the pace of implementation for definitive clinical practice is still moderate. It is worth looking at the currently recruiting trials (see Regarding the question of this editorial, “Can we efficiently target HDAC in cancer?”, the answer after summarizing the main results and conclusions of the published manuscript in this special issue is a clear “yes”. Yes, we can target HDAC in human cancer in a specific matter in order to adequately induce tumor-related cytotoxicity alone or possibly better in a combinatory strategy ,15,16,17ials see : HDAC inNevertheless, there is still a definitive need for action here to obtain more insights concerning the efficacy of HDACis in humans regarding polypharmacy and combinatory treatment strategies in relation to timing, sequencing, and intensity .Therefore, the articles in this Special Issue are intended to give some potential mechanistic insights of HDAC inhibitor using in vitro experiment with the aggressive tumor entities of biliary tract cancer, acute myeloid leukemia and chondrosarcoma. Furthermore, additional comprehensive reviews could demonstrate how HDACs are definitively involved in human cancerogenesis and how the new approach of polypharmacy could help to overcome deregulated epigenetics by specifically targeting HDACs. We sincerely hope that the articles in this Special Issue will inspire the cancers audience to enforce our common fight against human cancer now and in the future and to give the cancer suffering patients more hope for potential healing.


The selection of genetically superior animals for residual feed intake (RFI) does not affect animal growth, reproduction or the meat quality but it does lead to animals with lower consumption and lower maintenance requirements. This trait is difficult and costly to measure and is influenced by different biological processes and multiple genes. We used the RNA seq methodology of the liver in Nellore cattle with divergent RFI in two genetic groups. Eighty-eight common, differentially-expressed genes were identified in the two genetic groups. We highlight the B2M gene participating in most cellular processes that differentiate groups with a greater or lesser food efficiency. The biological pathways associated with RFI in the two genetic groups were for energy metabolism, protein turnover, redox homeostasis and the immune response. Additionally, we found non-coding RNAs, highlighting microRNA 25, which can act by blocking cytotoxicity and oxidative stress, and RNase_MRP, as a blocker of mitochondrial damage. This work could help future approaches in quantitative methods of animal husbandry and management and allow the use of possible markers for selecting more efficient animals, thus helping meat production costs and environmental impacts.n = 10 versus HRFI, n = 10) were selected from 83 animals. The raw data of the G2 were chosen from the ENA repository. A total of 1811 DEGs were found for the G1 and 2054 for the G2 . We detected 88 common genes in both genetic groups, of which 33 were involved in the immune response and in blocking oxidative stress. In addition, seven  possible gene biomarkers were identified through a receiver operating characteristic analysis (ROC) considering an AUC > 0.70. The B2M gene was overexpressed in the LRFI group. This gene regulates the lipid metabolism protein turnover and inhibits cell death. We also found non-coding RNAs in both groups. MIR25 was up-regulated and SNORD16 was down-regulated in the LRFI for G1. For G2, up-regulated RNase_MRP and SCARNA10 were found. We highlight MIR25 as being able to act by blocking cytotoxicity and oxidative stress and RMRP as a blocker of mitochondrial damage. The biological pathways associated with RFI of the liver in Nellore cattle in the two genetic groups were for energy metabolism, protein turnover, redox homeostasis and the immune response. The common transcripts, biomarkers and metabolic pathways found in the two genetic groups make this unprecedented work even more relevant, since the results are valid for different herds raised in different ways. The results reinforce the biological importance of these known processes but also reveal new insights into the complexity of the liver tissue transcriptome of Nellore cattle.The identification and selection of genetically superior animals for residual feed intake (RFI) could enhance productivity and minimize environmental impacts. The aim of this study was to use RNA-seq data to identify the differentially expressed genes (DEGs), known non-coding RNAs (ncRNAs), specific biomarkers and enriched biological processes associated with RFI of the liver in Nellore cattle in two genetic groups. In genetic group 1 (G1), 24 extreme RFI animals (12 low RFI (LRFI) versus 12 high RFI (HRFI)) were selected from a population of 60 Nellore bulls. The RNA-seq of the samples from their liver tissues was performed using an Illumina HiSeq 2000. In genetic group 2 (G2), 20 samples of liver tissue of Nellore bulls divergent for RFI (LRFI,  The world population is concerned about the environment and fulfilling the Sustainable Development Goals (SDGs), such as SDG 13 (Climate Action); moreover, growing pressure from the media is putting the focus, in recent times, on livestock. Thirty-seven percent of greenhouse gas (GHG) emissions are partly brought about by the global food supply even though the world population, particularly the high-income countries, has been recommended to reduce the global meat consumption , despiteFeed intake on farms is approximately 60% of the total cost of a livestock farm, therefore, a selection of more efficient animals would reduce the production costs and increase the profitability of the agricultural system . ResiduaThe identification and selection of genetically superior animals for their RFI would reduce feed costs, thereby increasing profits and minimizing the environmental impact ,16,17. TBos Indicus Cattle ..B2M as tGenetic group 1 showed a signaling pathway receptor activation via STAT that could have come from the activation transforming growth factor beta production, subsequently activating the ERK1 and ERK2 cascade, resulting in greater cell proliferation . Growth The liver has potential functions in controlling the variation in feed efficiency , but litMore efficient cattle may have a better response to inflammation and they may expend less energy fighting pathogens than heifers with a high RFI, while they also respond differently to pro-inflammatory hepatic stimuli and can have more energy available for muscle growth and deposition . FurtherHowever, the immune response is said to be an energetically-costly process, which generates fewer nutrients available for growth  and can The central dogma of molecular biology states that RNA functions revolve around protein translation, namely, the messenger RNAs (mRNAs), as temporary copies of genetic information, and ribosomal RNAs (rRNAs), as a main component of ribosome, or translators of the codon sequence (tRNAs). It is now known that this process represents less than 2% of the genome, and this insufficiently explains the functionality of 98% of the RNA transcripts . The ENCMicroRNAs act by regulating the expression of genes that drive numerous cellular processes. MIR25 is involved in biological processes such as the DNA damage response, cell cycle regulation, cell proliferation, migration and differentiation. In addition, many MIR25 target molecules can be found among the extracellular matrix components and membrane receptors . It alsoThe other small non-coding RNAs observed were SNORD16, which are down-regulated in LRFI. SnoRNAs are predominately found in the nucleolus, and mainly function as guide RNAs for the post-transcriptional modification of ribosomal RNAs. The SNORD16 are categorized according to the modification type as box H/ACA snoRNAs and are associated with rRNA pseudouridylation . The oveLong non-coding RNA (lncRNA) are thought to play a role in controlling gene expression in livestock species . FurtherSCARNA10 is a lncRNA transcript detected in G2. Hepatic fibrosis is characterized by the accumulation of excessive amounts of extracellular matrix components in the liver. This gene could be relevant in liver fibrosis ; howeverThe last detected long non-coding was RNase_MRP l in G2, which is an RNA component of mitochondrial RNA processing endoribonuclease (RMRP). RMRP is a recognized non-coding transcript  which inEighty-eight common DEGs were identified in the two genetic groups. The biomarkers relevant to our trait in liver tissue were identified as B2M, ADSS, SNX2, TUBA4A, ARHGAP18, MECR, and ABCF3, with the over-expressed B2M gene participating in most cellular processes that differentiated the groups with a greater or lesser food efficiency. The biological pathways associated with RFI of the liver in Nellore cattle in the two genetic groups were energy metabolism, protein turnover, redox homeostasis and the immune response. The common transcripts, biomarkers and metabolic pathways found in the two genetic groups make this unprecedented work even more relevant, since the results are valid for different herds raised and slaughtered in different ways. We found up-regulated MIR25 and down-regulated SNORD16 non-coding RNAs in the RLFI for G1. G2 exhibited up-regulated RNase_MRP and SCARNA10. We highlight MIR25 which can act by blocking cytotoxicity and oxidative stress and RMRP as a blocker of mitochondrial damage. These results reinforce the biological importance of these known processes but also reveal new insights into the complexity of the liver tissue transcriptome of Nellore cattle.