Surface nanocoating of bacteria as a versatile platform to develop living therapeutics.

Bacteria have been extensively utilized as living therapeutics for disease treatment due to their unique characteristics, such as genetic manipulability, rapid proliferation and specificity to target disease sites. Various in vivo insults can, however, decrease the vitality of dosed bacteria, leading to low overall bioavailability. Additionally, the innate antigens on the bacterial surface and the released toxins and metabolites may cause undesired safety issues. These limitations inevitably result in inadequate treatment outcomes, thereby hindering the clinical transformation of living bacterial therapeutics. Recently, we have developed a versatile platform to prepare advanced living bacterial therapeutics by nanocoating bacteria individually via either chemical decoration or physical encapsulation, which can improve bioavailability and reduce side effects for enhanced microbial therapy. Here we use interfacial self-assembly to prepare lipid membrane-coated bacteria (LCB), exhibiting increased resistance against a variety of harsh environmental conditions owing to the nanocoating's protective capability. Meanwhile, we apply mechanical extrusion to generate cell membrane-coated bacteria (CMCB), displaying improved biocompatibility owing to the nanocoating's shielding effect. We describe their detailed preparation procedures and demonstrate the expected functions of the coated bacteria. We also show that following oral delivery and intravenous injection in mouse models, LCB and CMCB present appealing potential for treating colitis and tumors, respectively. Compared with bioengineering that lacks versatile molecular tools for heterogeneous expression, the surface nanocoating technique is convenient to introduce functional components without restriction on bacterial strain types. Excluding bacterial culture, the fabrication of LCB takes ~2 h, while the preparation of CMCB takes ~5 h.

Cubic Na0.5Bi0.5TiO3 nanoperovskite significantly expands the application of sensitive immunosensor for the detection of carcinoembryonic antigen.

Nanosized sodium bismuth perovskite titanate (NBT) was synthesized and first used as the electrochemical immune sensing platform for the sensitive detection of carcinoembryonic antigen (CEA). Gold nanoparticles (Au NPs) grew on the surface of NBT through forming Au-N bond to obtain Au@NBT, and a label-free electrochemical immunosensor was proposed using Au@NBT as an immunosensing recognizer towards CEA. The well-ordered crystal structure of NBT was not changed at all after the modification of Au NPs outside, but significantly improved the conductivity, catalytic activity, and biocompatibility of the Au@NBT-modified electrode. The unique cubic crystal nanostructure of NBT offered a large active area for both Au NP modification and the subsequent immobilization of biomolecules over the electrode surface, triggering the effective generation of promising properties of the proposed Au@NBT-based electrochemical immunosensor. As expected, favorable detection performances were achieved using this immunosensor towards CEA detection, where a good linear relationship between the current response and CEA concentration was obtained in the concentration range 10 fg mL-1 to 100 ng mL-1 with a low detection limit (LOD) of 13.17 fg mL-1. Also, the significantly enhanced selectivity, and stability guaranteed the promising electrochemical properties of this immunosensor. Furthermore, the analysis of real serum samples verified the high feasibility of this new method in clinical CEA detection. This work opens a new window for the application of nanoperovskite in the early detection of CEA.

Reinforcement of the intestinal mucosal barrier via mucus-penetrating PEGylated bacteria.

The breakdown of the gut's mucosal barrier that prevents the infiltration of microorganisms, inflammatory cytokines and toxins into bodily tissues can lead to inflammatory bowel disease and to metabolic and autoimmune diseases. Here we show that the intestinal mucosal barrier can be reinforced via the oral administration of commensal bacteria coated with poly(ethylene glycol) (PEG) to facilitate their penetration into mucus. In mice with intestinal homoeostatic imbalance, mucus-penetrating PEGylated bacteria preferentially localized in mucus at the lower gastrointestinal tract, inhibited the invasion of pathogenic bacteria, maintained homoeostasis of the gut microbiota, stimulated the secretion of mucus and the expression of tight junctions, and prevented the mice from developing colitis and diabetes. Orally delivered PEGylated bacteria may help prevent and treat gastrointestinal disorders.

Gallic Acid-Modified Polyethylenimine-Polypropylene Carbonate-Polyethylenimine Nanoparticles: Synthesis, Characterization, and Anti-Periodontitis Evaluation.

The aim of the research was to develop novel gallic acid (GA)-modified amphiphilic nanoparticles of polyethylenimine (PEI)-polypropylene carbonate (PPC)-PEI (PEPE) and comprehensively assess its properties as an antiperiodontitis nanoparticle targeting the Toll-like receptor (TLR). The first step is to evaluate the binding potential of GA to the core trigger receptors TLR2 and TLR4/MD2 for periodontitis using molecular docking techniques. Following this, we conducted NMR, transmission electron microscopy, and dynamic light scattering analyses on the synthesized PEPE nanoparticles. As the final step, we investigated the synthetic results and in vitro antiperiodontitis properties of GA-PEPE nanoparticles. The investigation revealed that GA exhibits potential for targeted binding to TLR2 and the TLR4/MD2 complex. Furthermore, we successfully developed 91.19 nm positively charged PEPE nanoparticles. Spectroscopic analysis indicated the successful synthesis of GA-modified PEPE. Additionally, CCK8 results demonstrated that GA modification significantly reduced the biotoxicity of PEPE. The in vitro antiperiodontitis properties assessment illustrated that 6.25 µM of GA-PEPE nanoparticles significantly reduced the expression of pro-inflammatory factors TNF-α, IL-1ß, and IL-6. The GA-PEPE nanoparticles, with their targeted TLR binding capabilities, were found to possess excellent biocompatibility and antiperiodontitis properties. GA-PEPE nanoparticles will provide highly innovative input into the development of anti- periodontitis nanoparticles.

Hydrangea-like TiO2/Bi2MoO6 porous nanoflowers triggering highly sensitive electrochemical immunosensing to tumor marker.

Rapid and sensitive detection of carcinoembryonic antigen (CEA) is of great significance for cancer patients. Here, molybdenum (Mo) was doped into bismuth oxide (Bi2O3) by one-pot hydrothermal method forming porous tremella Bi2MoO6 nanocomposites with a larger specific surface area than the spherical structure. Then, a new kind of hydrangea-like TiO2/Bi2MoO6 porous nanoflowers (NFs) was prepared by doping titanium into Bi2MoO6, where titanium dioxide (TiO2) grew in situ on the surface of Bi2MoO6 nanoparticles (NPs). The hydrangea-like structure provides larger specific surface area, higher electron transfer ability and biocompatibility as well as more active sites conducive to the attachment of anti-carcinoembryonic antigen (anti-CEA) to TiO2/Bi2MoO6 NFs. A novel label-free electrochemical immunosensor was then constructed for the quantitative detection of CEA using TiO2/Bi2MoO6 NFs as sensing platform, showing a good linear relationship with CEA in the concentration range 1.0 pg/mL ~ 1.0 mg/mL and a detection limit of 0.125 pg/mL (S/N = 3). The results achieved with the designed immunosensor are comparable with many existing immunosensors used for the detection of CEA in real samples.

Upconversion dual-photosensitizer-expressing bacteria for near-infrared monochromatically excitable synergistic phototherapy.

Synergistic phototherapy stands for superior treatment prospects than a single phototherapeutic modality. However, the combined photosensitizers often suffer from incompatible excitation mode, limited irradiation penetration depth, and lack of specificity. We describe the development of upconversion dual-photosensitizer-expressing bacteria (UDPB) for near-infrared monochromatically excitable combination phototherapy. UDPB are prepared by integrating genetic engineering and surface modification, in which bacteria are encoded to simultaneously express photothermal melanin and phototoxic KillerRed protein and the surface primary amino groups are derived to free thiols for biorthogonal conjugation of upconversion nanoparticles. UDPB exhibit a near-infrared monochromatic irradiation-mediated dual-activation characteristic as the photothermal conversion of melanin can be initiated directly, while the photodynamic effect of KillerRed can be stimulated indirectly by upconverted visible light emission. UDPB also show living features to colonize hypoxic lesion sites and inhibit pathogens via bacterial community competition. In two murine models of solid tumor and skin wound infection, UDPB separately induce robust antitumor response and a rapid wound healing effect.

A New Non-Obese Steatohepatitis Mouse Model with Cardiac Dysfunction Induced by Addition of Ethanol to a High-Fat/High-Cholesterol Diet.

Non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) has been associated with cardiovascular-related mortality, leading to a higher mortality rate compared to the general population. However, few reports have examined cardiovascular events in non-obese MASLD mouse models. In this study we created a mouse model to mimic this condition. In this study involving seven-week-old C57BL/6J male mice, two dietary conditions were tested: a standard high-fat/high-cholesterol diet (STHD-01) and a combined diet of STHD-01 and ethanol. Over periods of 6 and 12 weeks, we analyzed the effects on liver and cardiac tissues using various staining techniques and PCR. Echocardiography and blood tests were also performed to assess cardiac function and liver damage. The results showed that mice on the ethanol-supplemented STHD-01 diet developed signs of steatohepatitis and cardiac dysfunction, along with increased sympathetic activity, as early as 6 weeks. At 12 weeks, more pronounced exacerbations accompanied with cardiac dilation, advanced liver fibrosis, and activated myocardial fibrosis with sympathetic activation were observed. This mouse model effectively replicated non-obese MASLD and cardiac dysfunction over a 12-week period using a combined diet of STHD-01 and ethanol. This dietary approach highlighted that both liver inflammation and fibrosis, as well as cardiac dysfunction, could be significantly worsened due to the activation of the sympathetic nervous system. Our results indicate that alcohol, even when completely metabolized on the day of drinking, exacerbates the progression of non-obese MASLD and cardiac dysfunction.

Dopamine Polymerization-Mediated Surface Functionalization toward Advanced Bacterial Therapeutics.

Bacteria-based therapy has spotlighted an unprecedented potential in treating a range of diseases, given that bacteria can be used as both drug vehicles and therapeutic agents. However, the use of bacteria for disease treatment often suffers from unsatisfactory outcomes, due largely to their suboptimal bioavailability, dose-dependent toxicity, and low targeting colonization. In the past few years, substantial efforts have been devoted to tackling these difficulties, among which methods capable of integrating bacteria with multiple functions have been extensively pursued. Different from conventional genetic engineering and modern synthetic bioengineering, surface modification of bacteria has emerged as a simple yet flexible strategy to introduce different functional motifs. Polydopamine, which can be easily formed via in situ dopamine oxidation and self-polymerization, is an appealing biomimetic polymer that has been widely applied for interfacial modification and functionalization. By virtue of its catechol groups, polydopamine can be efficiently codeposited with a multitude of functional elements on diverse surfaces.In this Account, we summarize the recent advances from our group with a focus on the interfacial polymerization-mediated functionalization of bacteria for advanced microbial therapy. First, we present the optimized strategy for bacterial surface modification under cytocompatible conditions by in situ dopamine polymerization. Taking advantage of the hydrogen bonding, π-π stacking, Michael addition, and Schiff base reaction with polydopamine, diverse functional small molecules and macromolecules are facilely codeposited onto the bacterial surface. Namely, monomodal, dual-modal, and multimodal surface modification of bacteria can be achieved by dopamine self-deposition, codeposition with a unitary composition, and codeposition with a set of multiple components, respectively. Second, we outline the regulation of bacterial functions by surface modification. The formed polydopamine surface endows bacteria with the ability to resist in vivo insults, such as gastrointestinal tract stressors and immune clearance, resulting in greatly improved bioavailability. Integration with specific ligands or therapeutic components enables the modified bacteria to increase targeting accumulation and colonization at lesion sites or play synergistic effects in disease treatment. Bacteria codeposited with different bioactive moieties, such as protein antigens, antibodies, and immunoadjuvants, are even able to actively interact with the host, particularly to elicit immune responses by either suppressing immune overactivation to promote the reversion of pathological inflammations or provoking protective innate and/or adaptive immunity to inhibit pathogenic invaders. Third, we highlight the applications of surface-modified bacteria as multifunctional living therapeutics in disease treatment, especially alleviating inflammatory bowel diseases via oral delivery and intervening in different types of cancer through systemic or intratumoral injection. Finally, we discuss the challenges and prospects of dopamine polymerization-mediated multifunctionalization for preparing advanced bacterial therapeutics as well as their bench to bedside translation. We anticipate that this Account can provide an insightful overview of bacterial therapy and inspire innovative thinking and new efforts to develop next-generation living therapeutics for treating various diseases.

Bacteria-based drug delivery for treating non-oncological diseases.

Bacteria inhabit all over the human body, especially the skin, gastrointestinal tract, respiratory tract, urogenital tract, as well as specific lesion sites, such as wound and tumor. By leveraging their distinctive attributes including rapid proliferation, inherent abilities to colonize various biointerfaces in vivo and produce diverse biomolecules, and the flexibility to be functionalized via genetic engineering or surface modification, bacteria have been widely developed as living therapeutic agents, showing promising potential to make a great impact on the exploration of advanced drug delivery systems. In this review, we present an overview of bacteria-based drug delivery and its applications in treating non-oncological diseases. We systematically summarize the physiological positions where living bacterial therapeutic agents can be delivered to, including the skin, gastrointestinal tract, respiratory tract, and female genital tract. We discuss the success of using bacteria-based drug delivery systems in the treatment of diseases that occur in specific locations, such as skin wound healing/infection, inflammatory bowel disease, respiratory diseases, and vaginitis. We also discuss the advantages as well as the limitations of these living therapeutics and bacteria-based drug delivery, highlighting the key points that need to be considered for further translation. This review article may provide unique insights for designing next-generation bacteria-based therapeutics and developing advanced drug delivery systems.

Generating dual structurally and functionally skin-mimicking hydrogels by crosslinking cell-membrane compartments.

The skin is intrinsically a cell-membrane-compartmentalized hydrogel with high mechanical strength, potent antimicrobial ability, and robust immunological competence, which provide multiple protective effects to the body. Methods capable of preparing hydrogels that can simultaneously mimic the structure and function of the skin are highly desirable but have been proven to be a challenge. Here, dual structurally and functionally skin-mimicking hydrogels are generated by crosslinking cell-membrane compartments. The crosslinked network is formed via free radical polymerization using olefinic double bond-functionalized extracellular vesicles as a crosslinker. Due to the dissipation of stretching energy mediated by vesicular deformation, the obtained compartment-crosslinked network shows enhanced mechanical strength compared to hydrogels crosslinked by regular divinyl monomers. Biomimetic hydrogels also exhibit specific antibacterial activity and adequate ability to promote the maturation and activation of dendritic cells given the existence of numerous extracellular vesicle-associated bioactive substances. In addition, the versatility of this approach to tune both the structure and function of the resulting hydrogels is demonstrated through introducing a second network by catalyst-free click reaction-mediated crosslinking between alkyne-double-ended polymers and azido-decorated extracellular vesicles. This study provides a platform to develop dual structure- and function-controllable skin-inspired biomaterials.

An Oral Nanomedicine Elicits In Situ Vaccination Effect against Colorectal Cancer.

Oral administration is the most preferred approach for treating colon diseases, and in situ vaccination has emerged as a promising cancer therapeutic strategy. However, the lack of effective drug delivery platforms hampered the application of in situ vaccination strategy in oral treatment of colorectal cancer (CRC). Here, we construct an oral core-shell nanomedicine by preparing a silk fibroin-based dual sonosensitizer (chlorin e6, Ce6)- and immunoadjuvant (imiquimod, R837)-loaded nanoparticle as the core, with its surface coated with plant-extracted lipids and pluronic F127 (p127). The resultant nanomedicines (Ce6/R837@Lp127NPs) maintain stability during their passage through the gastrointestinal tract and exert improved locomotor activities under ultrasound irradiation, achieving efficient colonic mucus infiltration and specific tumor penetration. Thereafter, Ce6/R837@Lp127NPs induce immunogenic death of colorectal tumor cells by sonodynamic treatment, and the generated neoantigens in the presence of R837 serve as a potent in situ vaccine. By integrating with immune checkpoint blockades, the combined treatment modality inhibits orthotopic tumors, eradicates distant tumors, and modulates intestinal microbiota. As the first oral in situ vaccination, this work spotlights a robust oral nanoplatform for producing a personalized vaccine against CRC.

Bacteria-Based Living Probes: Preparation and the Applications in Bioimaging and Diagnosis.

Bacteria can colonize a variety of in vivo biointerfaces, particularly the skin, nasal, and oral mucosa, the gastrointestinal tract, and the reproductive tract, but also target specific lesion sites, such as tumor and wound. By virtue of their prominent characteristics in motility, editability, and targeting ability, bacteria carrying imageable agents are widely developed as living probes for bioimaging and diagnosis of different diseases. This review first introduces the strategies used for preparing bacteria-based living probes, including biological engineering, chemical modification, intracellular loading, and optical manipulation. It then summarizes the recent progress of these living probes for fluorescence imaging, near-infrared imaging, ultrasonic imaging, photoacoustic imaging, magnetic resonance imaging, and positron emission tomography imaging. The biomedical applications of bacteria-based living probes are also reviewed particularly in the bioimaging and diagnosis of bacterial infections, cancers, and intestine-associated diseases. In addition, the advantages and challenges of bacteria-based living probes are discussed and future perspectives are also proposed. This review provides an updated overview of bacteria-based living probes, highlighting their great potential as a unique yet versatile platform for developing next-generation imageable agents for intelligent bioimaging, diagnosis, and even therapy.

Dual-Antigen-Displaying Nanovaccines Elicit Synergistic Immunoactivation for Treating Cancer and Preventing Infectious Complications.

As one of the most common complications, infection causes the majority of mortality in cancer patients. However, therapeutic strategies that can simultaneously suppress tumors and protect patients from infection have been rarely reported. Here, the use of dual-antigen-displaying nanovaccines (DADNs) is described to elicit synergistic immunoactivation for treating cancer and preventing infectious complications. DADNs are prepared by wrapping immunoadjuvant-loaded nanoparticles with a hybrid coating, which is fused from cell membranes that are separately genetically engineered to express tumor and infectious pathogenic antigens. Due to the presence of a dual-antigen combination, DADNs are able to promote the maturation of dendritic cells and more importantly to trigger cross-presentation of both combined antigens. During in vivo investigations, we find that DADNs can reverse immunosuppression by stimulating tumor-associated antigen-specific T-cell responses, resulting in significantly delayed tumor growth in mice. These nanovaccines also elicit effective protective immunity against tumor challenges and induce robust production of pathogenic antigen-specific immunoglobulin G antibody in a prophylactic study. This work offers a unique approach to develop dual-mode vaccines, which are promising for synchronously treating cancer and preventing infection.

Triggerable Prodrug Nanocoating Enables On-Demand Activation of Microbial and Small-Molecular Therapeutics for Combination Treatment.

The synergy of living microbial and small-molecular therapeutics has been widely explored for treating a variety of diseases, while current combination strategies often suffer from low bioavailability, heterogeneous spatiotemporal distribution, and premature drug release. Here, the use of a triggerable prodrug nanocoating is reported to enable the on-demand activation of microbial and small-molecular therapeutics for combination treatment. As a proof-of-concept study, a reactive oxygen species-responsive aromatic thioacetal linker is employed to prepare cationic chitosan-drug conjugates, which can form a nanocoating on the surface of living bacteria via electrostatic interaction. Following administration, the wrapped bacteria can be prevented from in vivo insults by the shielding effect of the nanocoating and be co-delivered with the conjugated drug in a spatiotemporally synchronous manner. Upon reaching the lesion site, the upgraded reactive oxygen species trigger in situ cleavage of the thioacetal linker, resulting in the release of the conjugated drug and a linker-derived therapeutic cinnamaldehyde. Meanwhile, a charge reversal achieved by the generation of negatively charged thiolated chitosan induces the dissociation of the nanocoating, leading to synchronous release of the living bacteria. The adequate activation of the combined therapeutics at the lesion site exhibits superior synergistic treatment efficacy, as demonstrated by an in vivo assessment using a mouse model of colitis. This work presents an appealing approach to combine living microbial and small-molecular therapeutics for advanced therapy of diseases.

Quercetin promotes the secretion of musk by regulating the hormone level and microbial structure of forest musk deer.

Musk is a scarce and precious medical resource secreted by male forest musk deer (FMD). Current research to promote musk secretion in FMD has used almost exclusively hormone injections, but this approach can be detrimental to the health of FMD. In order to conserve this endangered species as much as possible while increasing the production of musk, this study first used bioinformatics methods to predict the function of quercetin, a flavonoid that promotes testosterone (T) production and prevents late-onset male hypogonadism. On the basis of good prediction effect, different concentrations of quercetin were added to the diet of FMD. The results showed that quercetin could change the levels of T, luteinizing hormone releasing hormone, luteinizing hormone, and estradiol, and regulate the structure of intestinal microorganisms and musk microorganisms of FMD. Moreover, there is a correlation among musk components, hormones, intestinal microorganisms, and musk microorganisms, which indicates that the production of musk may be regulated by these three at the same time, and the addition of quercetin with 800 mg per kg diet could significantly increase the yield of muscone (P < 0.05), the most effective ingredient in musk. In addition, quercetin decreased the high level of cortisol during musk secretion, which may relieve the stress on FMD in this process. This may help to protect the health of FMD. Combined with the results of software prediction, we finally proposed a possible mechanism for the complex process of musk secretion in FMD with a view to providing ideas for further studies.

Surface-modified bacteria: synthesis, functionalization and biomedical applications.

The past decade has witnessed a great leap forward in bacteria-based living agents, including imageable probes, diagnostic reagents, and therapeutics, by virtue of their unique characteristics, such as genetic manipulation, rapid proliferation, colonization capability, and disease site targeting specificity. However, successful translation of bacterial bioagents to clinical applications remains challenging, due largely to their inherent susceptibility to environmental insults, unavoidable toxic side effects, and limited accumulation at the sites of interest. Cell surface components, which play critical roles in shaping bacterial behaviors, provide an opportunity to chemically modify bacteria and introduce different exogenous functions that are naturally unachievable. With the help of surface modification, a wide range of functionalized bacteria have been prepared over the past years and exhibit great potential in various biomedical applications. In this article, we mainly review the synthesis, functionalization, and biomedical applications of surface-modified bacteria. We first introduce the approaches of chemical modification based on the bacterial surface structure and then highlight several advanced functions achieved by modifying specific components on the surface. We also summarize the advantages as well as limitations of surface chemically modified bacteria in the applications of bioimaging, diagnosis, and therapy and further discuss the current challenges and possible solutions in the future. This work will inspire innovative design thinking for the development of chemical strategies for preparing next-generation biomedical bacterial agents.

Anti-inflammatory effect and mechanism of catalpol in various inflammatory diseases.

Catalpol is a kind of iridoid glucoside, widely found in a variety of plants, mostly extracted from the rhizome of the traditional medicinal herb rehmanniae. It has various biological activities such as anti-inflammatory, antioxidant, and antitumor. The anti-inflammatory effects of catalpol have been demonstrated in a variety of diseases, such as neurological diseases, atherosclerosis, renal diseases, respiratory diseases, digestive diseases, bone and joint diseases, eye diseases, and periodontitis. The purpose of this review is to summarize the existing literature on the anti-inflammatory effects of catalpol in a variety of inflammatory diseases over the last decade and to focus on the anti-inflammatory mechanisms of catalpol.

Nanomaterial-based ophthalmic drug delivery.

The low bioavailability and side effects of conventional drugs for eye disease necessitate the development of efficient drug delivery systems. Accompanying the developments of nanofabrication techniques, nanomaterials have been recognized as promising tools to overcome these challenges due to their flexible and programmable properties. Given the advances achieved in material science, a broad spectrum of functional nanomaterials capable of overcoming various ocular anterior and posterior segment barriers have been explored to satisfy the demands for ocular drug delivery. In this review, we first highlight the unique functions of nanomaterials suitable for carrying and transporting ocular drugs. Then, various functionalization strategies are emphasized to endow nanomaterials with superior performance in enhanced ophthalmic drug delivery. The rational design of several affecting factors is essential for ideal nanomaterial candidates and is depicted as well. Lastly, we introduce the current applications of nanomaterial-based delivery systems in the therapy of different ocular anterior and posterior segment diseases. The limitations of these delivery systems as well as potential solutions are also discussed. This work will inspire innovative design thinking for the development of nanotechnology-mediated strategies for advanced drug delivery and treatment toward ocular diseases.

In Situ Polymerization-Mediated Antigen Presentation.

Activating antigen-presenting cells is essential to generate adaptive immunity, while the efficacy of conventional activation strategies remains unsatisfactory due to suboptimal antigen-specific priming. Here, in situ polymerization-mediated antigen presentation (IPAP) is described, in which antigen-loaded nanovaccines are spontaneously formed and efficiently anchored onto the surface of dendritic cells in vivo through co-deposition with dopamine. The resulting chemically bound nanovaccines can promote antigen presentation by elevating macropinocytosis-based cell uptake and reducing lysosome-related antigen degradation. IPAP is able to prolong the duration of antigen reservation in the injection site and enhance subsequent accumulation in the draining lymph nodes, thereby eliciting robust antigen-specific cellular and humoral immune responses. IPAP is also applicable for different antigens and capable of circumventing the disadvantages of complicated preparation and purification. By implementation with ovalbumin, IPAP induces a significant protective immunity against ovalbumin-overexpressing tumor cell challenge in a prophylactic murine model. The use of the SARS-CoV-2 Spike protein S1 subunit also remarkably increases the production of S1-specific immunoglobulin G in mice. IPAP offers a unique strategy for stimulating antigen-presenting cells to boost antigen-specific adaptive responses and proposes a facile yet versatile method for immunization against various diseases.