Mechanoluminescence offers unique advantages over traditional photoluminescence, including deeper tissue penetration and minimal autofluorescence. However, mechanoluminescent materials typically lack the sensitivity and reusability of their biological counterparts. Inspired by the mechanoregulation of luciferase in dinoflagellate scintillons, we develop a scintillon-mimetic mechanoluminescent nanoreactor (sMLN) by integrating mechanoresponsive ferrocene (Fc) moieties into a flexible organic silica vesicle. Under ultrasound (US) irradiation, acoustic shear forces stretch and twist the Fc moiety, increasing the Fe center electron density and reducing steric hindrance, thereby facilitating substrate binding and activating a Fenton-like reaction that triggers luminol-based luminescence. Unlike conventional mechanoluminescent materials, sMLNs exhibit repeatable and long-lasting luminescence with a half-life of approximately 5.73 min, leading to a ∼2.2 × 103-fold enhancement in intensity compared to H2O sonoluminescence. This US-induced mechanoluminescence functions as an "internal light source" to excite the chromophore for bioimaging and photodynamic therapy, overcoming the limitations of light penetration depth. This high-performance platform enables intense and ultrasensitive mechanoluminescence, providing a powerful mechanochemical tool for advanced theranostic applications.

The combination of cancer vaccine and an immune checkpoint inhibitor (ICI) function synergistically to induce effective antitumor immune responses. However, their clinical application is constrained by exacerbated immune-related adverse events (irAEs), notably checkpoint inhibitor-associated pneumonitis (CIP). To address this challenge, a peripheral lymphoid organ-targeted strategy was developed to spatiotemporally modulate T-cell responses through the co-localization of tumor vaccines and anti-PD1 (αPD1). This approach substantially reduced tumor growth and CIP severity by attenuating nonspecific T-cell infiltration in the lungs. In contrast, when tumor vaccines and αPD1 failed to precisely target the same T cell population, the enhanced therapeutic efficacy was at the cost of increased off-target CIP. As a consequence, combined tumor-specific T cells with PD1-blockade performed superior tumor-specific cytotoxicity and preferential tumor infiltration, further augmenting anti-tumor effects while minimizing CIP. These findings provide a homologous lymphoid organ-targeted paradigm that optimizes anti-tumor immune responses with reduced immune-related toxicities, offering a promising strategy for safer and more effective cancer immunotherapy.

Intervertebral disc degeneration (IVDD) is characterized by overactive oxidative stress, uncontrolled inflammation, and the deterioration of extracellular matrix (ECM). Deciphering the spatiotemporal cues of the complicated microenvironment would facilitate the development of new therapeutic strategies. In this study, we reveal that increased expression of oxidative stress markers is strongly associated with pro-inflammatory markers at the early stage, whereas the level of ECM repair markers is elevated at the late stage. Hypothesizing that sequentially targeting redox, inflammation, and ECM repair would be beneficial to IVDD management, we report the development of diselenide-bridged mesoporous silica nanoparticles (MSNs) loaded with SDF-1α. Redox-responsive MSNs not only efficiently neutralize ROS in damaged nucleus pulposus (NP) cells and macrophages to ameliorate oxidative stress and inflammation at the early stage via inhibiting the NF-κB pathway, but also sequentially release SDF-1α to facilitate ECM repair at the late stage via activating the PI3K-AKT-mTOR pathway. Leveraging such a time-sequenced microenvironment regulation mechanism, MSN@SDF-1α attenuates inflammation, maintains NP water content, and induces mesenchymal stem cells (MSCs) homing, leading to the structural regeneration of intervertebral discs in a puncture model. Our study proposes a mechanism-driven therapeutic approach that integrates insights into redox, inflammation, and ECM repair with the advanced design of versatile bioactive materials, offering a promising strategy for precise intervertebral disc regeneration.

The limited efficacy of intraperitoneal chemotherapy for colorectal peritoneal metastases (CPM) arises from its failure to remodel the tumor-promoting microenvironment dominated by M2-like macrophages. Here, we demonstrate that anionic nanoparticles coloaded with regorafenib (REG) and paclitaxel (PTX) are capable of overcoming this limitation by not only directly killing tumor cells but also reprogramming macrophages to the antitumor phenotype. We uncovered that anionic nanoparticles achieved superior retention and more balanced in vivo uptake by both tumor cells and macrophages compared with their cationic or neutral counterparts. Then, we fabricated anionic 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) liposome-coated albumin-bound REG and PTX (DOPA@Alb-RP) and demonstrated that DOPA@Alb-RP treatment elicited potent and durable antitumor immunity and significantly prolonged survival in the mouse model of CPM. Impressively, the treatment achieved tumor eradication in 64% of the mice. This macrophage-engaging nanoplatform provides a rational approach to potentiating chemoimmunotherapy against peritoneal metastases.

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking defined molecular targets and characterized by high rates of recurrence and metastasis. Aberrant activation of the epidermal growth factor receptor (EGFR) contributes to tumor progression and immune evasion in TNBC. Although EGFR inhibitors can temporarily suppress tumor growth, compensatory signaling and therapeutic resistance limit their effectiveness. Therapeutic strategies that modulate multiple pathways while enhancing antitumor immunity are needed, and selective nanoparticle-based delivery offers a means to improve potency while reducing nonspecific toxicity. We developed ND-dsRNA-VHH, a biocompatible carbon-based nanomaterial platform that codelivers EGFR-specific nanobodies (VHHs) and immunostimulatory double-stranded RNA, polyinosinic-polycytidylic acid (poly(I:C)). Optimized ND surface chemistry supported efficient dsRNA payload and stable VHH conjugation, yielding nanoparticles with EGFR-binding specificity and serum stability. Subsequent studies demonstrated that ND-dsRNA-VHH induced apoptosis, oxidative stress, and immunogenic cell death, leading to dendritic cell activation. Additional assessments indicated that treatment with ND-dsRNA-VHH reduced tumor growth, extended survival, increased T-cell infiltration, and shifted the tumor microenvironment toward a more proinflammatory, immunologically active state. The modular nature of this platform supports ligand exchange for broader applicability across EGFR-driven malignancies such as glioblastoma, underscoring its potential to enhance immunotherapy through combined ICD induction and immune priming.

Drug-induced liver injury (DILI) is a complex and intractable disease because existing anti-oxidate therapies in clinic fail to modulate multiple pathological pathways concurrently. Here, we present a direction-aware framework that integrates disease-network analysis, AI-guided molecular screening, and self-assembled nanomedicine design for precise protection of DILI. Time-resolved transcriptomic profiling of DILI identifies two complementary repair axes: the suppression of cytokine-cytokine receptor signaling for inflammation control together with the activation of glutathione biosynthesis for antioxidant defense. Guided by these DILI-driven mechanisms, we develop a dual-constraint deep-learning model that jointly evaluates the interaction between therapeutic molecules and disease targets, enabling the identification of candidate molecules whose biological effects match the desired intervention. Through independent screening from FDA-approved active pharmaceutical ingredients pool, we explore hesperidin (HES) and ursodeoxycholic acid (UDCA) as combination molecules capable of self-assembling into uniform nanomedicines (HUNMs) with predicted biological activities. Flash nanocomplexation-based engineering of HES and UDCA produces stable carrier-free nanocrystals with improved aqueous dispersibility. In an acetaminophen-challenged DILI mice, HUNMs alleviate hepatic injury, suppress inflammatory responses, restore glutathione homeostasis, and accelerate liver recovery. Together, our insights highlight an AI-native strategy that harnesses smart molecules to develop a precise and translatable nanomedicine for efficient management of DILI and other complex diseases.

Danger signal dysregulation provides a unifying framework for understanding oral inflammatory diseases, which arise from the persistent accumulation of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), together with excessive oxidative stress-derived danger signals such as reactive oxygen species (ROS), which lead to chronic activation of inflammatory pathways within the uniquely dynamic oral microenvironment. This perspective highlights emerging danger signal-removing strategies—particularly immunoengineering materials and external physical stimuli-responsive platforms—that enable upstream modulation of inflammation, reprogramming of immune and stromal cell phenotypes, and restoration of microenvironmental homeostasis. By integrating specific interactions with spatiotemporal control, next-generation biomaterials offer a mechanistically grounded and clinically adaptable approach for effective and safe management of complex oral inflammatory disorders. Together, these advances chart a path toward adaptive, precise, and personalized biomaterials tailored to address the biological and physicochemical challenges of the oral cavity.

During the development of oral squamous cell carcinoma (OSCC), multiple danger signals can initiate chronic oral mucosal inflammation, which then gives rise to precancerous and cancerous lesions. Modulation of immune homeostasis is essential to intercept inflammation-driven OSCC. In this study, we aimed to identify key inflammatory danger signals involved in precancerous oral mucosal inflammation and to develop a locally applicable immunomodulatory strategy to prevent this precancerous inflammation. We first identified that saliva cell-free DNA (cfDNA) levels and cfDNA-induced TLR9 activation were linked to OSCC development and progression. Hypothesizing that removing cfDNA would be beneficial for OSCC prevention, we created a cationic nanoparticles-enabled mouthwash that regulates precancerous inflammation via removing negatively charged cfDNA. Both cationic nanoparticles and polymers inhibited the in vitro cellular proinflammatory response induced by plasma from OSCC patients and suppressed OSCC patient plasma-induced tumor cell migration and stemness. In the precancerous mouse model, cationic nanoparticles-enabled mouthwash alleviated oral mucosal inflammation via inhibiting TLR9 activation. Overall, our study highlights the role of cfDNA in OSCC progression and the potential of cationic nanoparticle-enabled mouthwash for treating OSCC-related precancerous oral mucosal inflammation.

Introduction:Sepsis, a life-threatening and costly condition, necessitates early detection for effective management. However, diagnostic and therapeutic delays are common. Furthermore, sepsis complexity and dynamics challenge existing early warning systems, impeding timely intervention. Methods:In this study, we introduce the Bayes-Optimized Boosting-Mamba Tab Model (BOBM), a novel deep learning-based algorithm that incorporates a bidirectional optimization learning mechanism within an ensemble framework. We designed dynamic agent models to enhance computational efficiency and adaptability across diverse clinical scenarios. Additionally, the model architecture was optimized for different temporal phases to enable a more precise estimation of the timing and progression of sepsis risk. To improve interpretability, we implemented SHapley Additive exPlanations value analysis, providing clinicians with actionable insights into potential patterns of sepsis progression. Results:The experimental evaluation demonstrated that our model attained the highest AUC (AUC: 0.86-0.95) in the MIMIC-IV dataset across different temporal windows prior to sepsis onset, confirming its adaptability and robust generalizability across various prediction timeframes. Furthermore, the model demonstrated superior performance (AUC: 0.978-0.982) when validated on two independent large-scale external datasets. Conclusion:In contrast to traditional prediction approaches, our model extends the potential intervention timeframe significantly, while incorporating dynamic monitoring capabilities spanning the 7- to 28-day window before clinical suspicion, thereby establishing a foundation for regional sepsis surveillance systems.

Chemotherapy remains the mainstay treatment for hepatocellular carcinoma (HCC), yet clinical outcomes have stagnated due to the inevitable reduction in chemosensitivity. Epigenetic engineering represents a promising avenue to enhance chemosensitivity, but facing limited understanding of its mechanism and lacking efficient chemical tools. Here, we identify aberrant overexpression of DNA methyltransferase 3B (DNMT3B), a key de novo DNA methyltransferase, as a functional driver of poor chemotherapeutic response in HCC. To exploit this epigenetic vulnerability, we developed a carrier-free nanoepidrug (termed DSNP) via the co-assembly of the chemotherapeutic agent doxorubicin (DOX) with the DNMT3B inhibitor SGI-1027 (SGI). The resulting DSNP exhibit ultrahigh active pharmaceutical ingredient loading (∼90 wt%) and a pH-responsive release profile tailored to the acidic tumor microenvironment. Mechanistically, DSNP markedly amplified DOX-induced DNA damage, consistent with SGI-mediated DNMT inhibition that remodelled chromatin into a more accessible state. This synergy increased chemosensitivity by more than tenfold and yielded a 92.5 % relative increase in tumor growth inhibition on HCC model. These findings highlight the potential of epigenetic-engineering to overcome chemoresistance, and provide a carrier-free nanomedicine to potentiate efficacy of HCC chemotherapy.

Mechanoenzymes, featuring catalytic activity controlled by mechanical stimuli, play key roles in maintaining metabolic order and cellular homeostasis. However, artificial nanozymes with strict spatiotemporal regulation are still rare, limiting their effectiveness in complex biological environments. Here, we introduce a mechanically regulated nanozyme (MRNZ) by integrating mechano-responsive ferrocene (Fc) units into a flexible framework. Similar to natural enzymatic activation, acoustic shear forces cause sub-nanostructural transformations of Fc units, leading to decreased electron density and reduced steric hindrance at Fe active sites, reinforcing metabolic peroxidase (POD)-like activity. This mechanical activation enables precise modulation of metabolic reprogramming by controlled generation of low-dose hydroxyl radicals (•OH) as second messengers, improving stem cells resilience to oxidative stress for safer and more effective therapeutic interventions. Using this mechanically regulated method, we encapsulated glucose oxidase (GOx) inside hollow MRNZ to create a multienzyme regulated nanoreactor (MRNZ@GOx) that orchestrates a cascade GOx-POD reaction under ultrasound stimulation. Such a cascade reactive oxygen species generation in tumor microenvironments potentiates chemodynamic therapy combined with immune activation. Our work introduces a mechanically responsive strategy for regulating nanozyme activity, expanding the horizons of next-generation remote and smart catalytic technologies for precise disease treatments.

Castration-resistant prostate cancer (CRPC) remains lethal due to adaptive resistance mechanisms such as stress-induced autophagy and NF-κB survival signaling. Here, an injectable fiber-in-hydrogel depot is developed for sequential delivery of a multi-enzyme nanozyme (cobalt-epigallocatechin gallate coordination nanozyme, CoNZ) and the lysosomal inhibitor chloroquine (CQ). The preferentially released CoNZ catalytically generates reactive oxygen species, including hydroxyl radicals, and oxygen in situ, inflicting oxidative damage while relieving tumor hypoxia. Simultaneously, it depletes antioxidants (glutathione, NADPH) and impedes NF-κB nuclear translocation, priming CRPC cells for apoptosis. The subsequently released CQ impedes enzymatic degradation or cleavage in endolysosomes and autolysosomes and blocks TLR9/NF-κB signaling, preventing tumor cells from repairing damage or activating pro-survival pathways. In vitro and in vivo, this two-pronged approach synergistically overcomes CRPC's defenses, achieving markedly enhanced cancer cell apoptosis and ∼80% tumor suppression (with occasional complete regression), resulting in an approximately 10-fold reduction in final tumor volume compared to the untreated control, without systemic toxicity, far surpassing single or co-administered treatments. This work demonstrates a spatiotemporally orchestrated combination of nanocatalytic therapy and lysosomal inhibition that dismantles CRPC's resistance mechanisms, highlighting a broadly applicable paradigm for overcoming therapeutic resistance in aggressive cancers.

Abstract Targeting the overwhelming inflammation driven by neutrophil extracellular traps (NETs) during infection provides an opportunity to manage severe sepsis. This potential needs to be realized by exploring selective NET-neutralization materials, which remains a challenge. Herein, we report a multivalent macromolecular strategy that targets NET-associated DNA-histone chromatin complexes while preserving antibacterial activity of aminoglycoside. We identify 8-arm PEG-conjugated netilmicin (8-arm Netil) as a lead NETs-neutralizer from a library of multivalent aminoglycoside-displayed materials. When compared with 2- and 4-arm counterparts, 8-arm Netil exhibits potent antibacterial activity and high-affinity binding to DNA-histone chromatin complexes through stable multivalent noncovalent interactions, thereby suppressing NET-induced TLR4/TLR9 activation and macrophage inflammatory responses. In severe septic mice, intravenously administered 8-arm Netil preferentially accumulates in inflamed tissues, leading to improved survival protection, owing to the reduction of bacterial dissemination, NET accumulation, systemic cytokine production, and multiple-organ injury. These findings establish NET-associated DNA-histone chromatin complexes as actionable extracellular targets and demonstrate multivalent chromatin targeting as a rational material design strategy for selective NET neutralization and inflammation control in severe sepsis.

Bacterial osteomyelitis remains a formidable challenge in clinic because existing monotherapies fail to block inevitable infection, uncontrolled inflammation, and impaired bone regeneration ‌concurrently. Here, we present an AI-assisted strategy that integrates antibacterial, anti-inflammatory, and pro-osteogenic activities into a single nanocrystal. Through machine learning‑assisted screening from FDA-approved active pharmaceutical ingredients (API), we identified glycyrrhizic acid and simvastatin as a multifunctional combination capable of self-assembling into uniform nanocrystals (SGNCs) with ultrahigh drug loading. SGNCs effectively neutralize reactive oxygen species, suppress M1 macrophage polarization, promote bactericidal effects, and reverse infection-impaired osteogenic differentiation. Mechanistically, RNA sequencing analysis further reveals that the beneficial effects of SGNCs are associated with the inhibition of inflammatory response via cytokine-cytokine receptor interaction pathway and the activation of bone regeneration program via the Wnt signaling pathway. As a consequence, SGNCs eradicate bacterial burden and restore bone microarchitecture with excellent biocompatibility in a rat osteomyelitis model. Our insights highlight an AI-assisted strategy that creates a mechanism-targeting nanomedicine solely from APIs for the efficient treatment of bacterial osteomyelitis, which currently requires multimodal management.

Acute liver injury is a life-threatening disorder associated with substantial morbidity and mortality worldwide, underscoring the need for convenient and minimally invasive monitoring. Here, we develop an ALI-responsive nanoprobe that dissociates into renal-clearable gold nanoparticles, facilitating minimally invasive acute liver injury diagnosis through colorimetric urinalysis. This nanoprobe is constructed as a simple nanoaggregate of self-assembled ultrasmall AuNPs linked via a responsive moiety (2,2'-[propane-2,2-diylbis(thio)]diacetic acid). Elevated endogenous reactive oxygen species in the injured liver trigger the dissociation of Au-TKs accumulated in hepatic tissue. The released AuNPs are subsequently excreted into urine and can be quantified by leveraging their peroxidase-like activity and renal-clearable property. This platform outperforms conventional serum-based methods in terms of sensitivity and accuracy for early prediction of acetaminophen-induced liver injury in mice. To enhance practicality, a smartphone application with color capture capability was developed, demonstrating excellent linearity (R2 > 0.95) compared with microplate reader detection. This smartphone-based colorimetric biosensing system, featuring convenient, minimally invasive operation, holds strong potential to transform ALI monitoring through urinary readouts and may provide additional benefits for rapid detection of a broad range of inflammatory diseases by targeting disease-specific pathological signatures.

Biofilms are the root of persistent infections, while photodynamic therapy (PDT) shows promise in biofilm eradication. However, extracellular polymeric substance matrix, together with hypoxic and acidic environments, hinder the penetration and bacterial elimination of photosensitizers. To address these challenges, this study reports a nano-photosensitizer (AgRu) that self-assembled via ruthenium‑silver conjugates to strengthen PDT-mediated biofilm clearance. The hydrophobic donor-π-acceptor architecture of nanophotosensitizer not only endows the strong affinity toward bacterial membranes and extracellular DNA (eDNA) for deep intra-biofilm penetration, but also enables the light-responsive release of antimicrobial Ag+ into the biofilm interior, together amplifying PDT efficacy. Meanwhile, such a Type I photosensitizer enables robust generation of reactive oxygen species (ROS), including O2− and ·OH, especially under hypoxic and acidic biofilm microenvironments. The overproduced ROS trigger lipid peroxidation and eDNA degradation concurrently in bacterial membranes, further destabilizing the biofilm matrix and promoting bacterial killing. Taking advantage of combined photodynamic biofilm disruption with targeted intra-biofilm antimicrobial delivery, AgRu markedly accelerate the healing of P. aeruginosa-infected wounds and alleviate bacterial keratitis in two murine models. Overall, this work establishes a synergistic strategy that couples lipid peroxidation and eDNA degradation, highlighting the potential of sophisticated nanophotosensitizer for the management of biofilm-associated infections.

In the field of diagnosing lung diseases, the application of neural networks (NNs) in image classification exhibits significant potential. However, NNs are considered “black boxes,” making it difficult to discern their decision-making processes, thereby leading to skepticism and concern regarding NNs. This compromises model reliability and hampers intelligent medicine's development. To tackle this issue, we introduce the Evolutionary Neural Architecture Search (EvoNAS). In image classification tasks, EvoNAS initially utilizes an Evolutionary Algorithm to explore various Convolutional Neural Networks, ultimately yielding an optimized network that excels at separating between redundant texture features and the most discriminative ones. Retaining the most discriminative features improves classification accuracy, particularly in distinguishing similar features. This approach illuminates the intrinsic mechanics of classification, thereby enhancing the accuracy of the results. Subsequently, we incorporate a Differential Evolution algorithm based on distribution estimation, significantly enhancing search efficiency. Employing visualization techniques, we demonstrate the effectiveness of EvoNAS, endowing the model with interpretability. Finally, we conduct experiments on the diffuse lung disease texture dataset using EvoNAS. Compared to the original network, the classification accuracy increases by 0.56%. Moreover, our EvoNAS approach demonstrates significant advantages over existing methods in the same dataset.

The development of high-performing photocatalysts with visible-light-absorbing and oxidative properties for the degradation of organic contaminants in anaerobic microenvironments remains a challenge. Herein, a Ru-complex decorated with coumarin ([Ru(phen)2Cur]Cl2) molecules was created to achieve high absorption capacities and photocatalytic activity. Taking advantage of the nanoparticulate structure, the transformation of [Ru(phen)2Cur]Cl2 molecules into Ru(II) nanostructures (RuCur NPs) not only exhibited an extensive broad visible-light absorption spectrum but also possessed enhanced intersystem crossing efficiency and improved electron transfer. Consequently, these self-assembled nanocatalysts performed efficient photodegradation toward both antibiotics and organic dyes, especially in acidic and anaerobic environments. Mechanistically, photoactivated electrons and holes on the surface of nanostructures drive the degradation of organic molecules via direct redox reactions in an oxygen-independent manner. This result proposed a fundamental insight for developing oxygen-independent nanoparticulate photocatalysts.

Selenium supplementation has potential in treating aging-related disorders like neurodegenerative and cardiovascular diseases, but its use is limited by poor bioavailability, a narrow therapeutic window, and unclear mechanisms. To overcome this, redox-dual-responsive diselenide-bridged mesoporous silica nanoparticles (SeMSNs) are developed. SeMSNs effectively reduce oxidative stress and downregulate senescence markers (p16, p21), suppressing senescence in both naturally aged primary mouse embryonic fibroblasts (MEFs) and H2O2-induced HEK-293T cells. They show prolonged antioxidant effects (p < 0.05) and lower cytotoxicity (p < 0.01) than commercial selenomethionine. In aged mice, SeMSNs extend lifespan, reduce frailty, and improve age-related conditions, including muscle atrophy, renal dysfunction, cognitive decline, and hepatic steatosis, while restoring metabolic balance. They outperform conventional organically-bridged mesoporous silica nanoparticles (MSNs) and disulfide-bridged MSNs (SMSNs) (p < 0.01). Mechanistically, SeMSNs upregulate selenoproteins (GPx1, SelK), suppress endoplasmic reticulum (ER) stress-mediated calcium release, maintain calcium homeostasis, and inhibit NFATc2-driven Sik1 transcription, reducing p21/p16. Clinical data confirm an inverse correlation between selenium levels and aging biomarkers (p < 0.0001). SeMSNs also restore adipogenic differentiation in human adipose progenitor cells via calcium-NFATc2-Sik1 signaling. These results demonstrate the superiority of SeMSNs over traditional selenium forms, providing a nanotherapeutic strategy to combat multi-organ aging and promote healthy longevity.

Mucosal immunity plays a pivotal role in safeguarding against significant global infectious diseases caused by mucosal pathogens. The development of mucosal vaccines has been limited by the poor efficiency of antigen display and the risk of adjuvants. Here, we report an engineered yeast vaccine integrating a well-displayed antigen with an intrinsic adjuvant for the development of innate and adaptive immunity to the intestinal mucosa. Compared with antigen-secretory yeast, antigen-anchored yeast significantly activated gut dendritic cells (DCs) and promoted follicular helper T (Tfh) cell differentiation, thereby amplifying the immune response by the interaction with Tfh-B cells. Consequently, oral vaccination of SARS-CoV-2 receptor-binding domain (RBD)-anchored yeast triggered stronger RBD-specific IgA-neutralizing effects, providing potential adaptive protections. Given its corresponding impact on the functionality of both innate and adaptive mucosal responses, the proposed RBD-anchored yeast outperformed RBD-anchored bacteria and biomimetic nanovaccine in the production of RBD-specific IgA and IgG. Together, these results revealed how antigen-displaying patterns could be modulated to elicit intestinal mucosal immunity and demonstrated the translational potential of antigen-displayed yeast for effective mucosal protection.