Synovial macrophage-mediated inflammation and mitochondrial dysfunction are increasingly implicated in osteoarthritis (OA) progression, yet targeted restoration of mitochondrial quality control remains challenging. Here, we developed a macrophage-targeted, targeted delivery nanoplatform (CBP-NPs@Song) by conjugating a CD80-binding peptide to songorine-loaded lipid nanoparticles for preferential and CD80-dependent delivery to proinflammatory (M1) macrophages. CBP-NPs@Song significantly enhanced intracellular drug accumulation and improved multiple indices of mitochondrial function and integrity in inflammatory macrophages. Mechanistically, songorine stabilized PINK1 by reducing its ubiquitination and proteasomal degradation, thereby activating the PINK1–Parkin mitophagy pathway, supporting enhanced clearance of damaged mitochondria through PINK1-associated mitochondrial quality-control processes, and suppressing NLRP3 inflammasome activation. Targeted mitochondrial regulation in macrophages attenuated the adverse effects of proinflammatory macrophages on co-cultured chondrocytes and protected chondrocytes from oxidative and inflammatory injury. In vivo, CBP-NPs@Song exhibited prolonged intra-articular retention with minimal systemic exposure, significantly attenuating synovial inflammation, osteophyte formation, and cartilage degeneration in OA rats. This study presents a targeted nanotherapeutic strategy that integrates selective immunomodulation with mitochondrial quality control, offering a potential strategy for structure-preserving and immunomodulatory OA therapy.
Bladder cancer therapy is frequently limited by inefficient drug retention and adaptive immune resistance within a hypoxic tumor microenvironment. Here, we report a CD44-targeted, fully synthetic nanocomposite (HPPZC) that converts chemotherapy into a mitochondria-associated therapeutic strategy accompanied by tumor immune remodeling. Rapid microwave-assisted assembly integrates hyaluronic acid (HA), polydopamine (PDA), protamine, zinc oxide (ZnO), and camptothecin (CPT) into a structurally integrated hybrid nanocomposite with tumor targeting, while the PDA/ZnO interface functions as a redox-active platform associated with mitochondrial dysfunction and redox modulation. HPPZC induces rapid mitochondrial depolarization, elevates oxidative stress, and is associated with PINK1/Parkin-related mitochondrial quality-control and autophagy-associated turnover signatures. In vivo, HPPZC treatment prolonged local intratumoral retention and produced tumor regression. The combination of chemotherapy with mitochondrial stress and tumor immune remodeling, suppressing CXCL12 and PD-L1, promoting M1-like marker profile, and increasing CD8⁺ T-cell infiltration. This work establishes a reproducibly fabricated redox-active nanotherapeutic associated with mitochondrial stress that couples targeted chemotherapy with immune microenvironment remodeling for antitumor efficacy.
Cuproptosis-based cancer immunotherapy is severely limited by hypoxia-associated metabolic resistance, immunosuppressive tumor microenvironments, and the lack of tumor-selective delivery of cuproptosis inducers. Herein, we developed a temporally coordinated therapeutic strategy by integrating a tumor-targeting nitric oxide (NO)-producing bacterial platform (ECN-NO) with ultrasound-responsive ES-Cu-loaded microbubbles (ES-Cu MBs) to sequentially remodel the tumor microenvironment and potentiate cuproptosis immunotherapy. ECN-NO selectively colonized tumors and continuously released NO, thereby normalizing tumor vasculature, alleviating hypoxia, and facilitating the intratumoral generation, delivery, and penetration of ES-Cu nanotherapeutics following ultrasound-responsive microbubble destruction (UTMD). The enhanced intratumoral accumulation of ES-Cu amplified cuproptosis-induced oxidative stress, which triggered bacterial lysis to both establish an arginine-dependent nitroxidative amplification cascade and intrinsically limit bacterial persistence, resulting in robust peroxynitrite (ONOO⁻) generation. Consequently, ONOO⁻ disrupted glutamine metabolism, reinforced cuproptosis, and potentiated immunological activation. This temporally coordinated strategy of tumor microenvironment remodeling, cuproptosis amplification, and immune activation elicited potent systemic antitumor immunity and durable immunological memory. Together, these findings establish a self-regulating bacterial–nanomedicine strategy for enhancing cuproptosis-based cancer immunotherapy.
The regeneration of diabetic bone defects represents a significant clinical challenge due to impaired osteogenesis, angiogenesis, and a chronic inflammation. To address this gap, our study introduced a novel “seed-and-soil” coordinative intervention paradigm. Leveraging metformin’s anti-inflammatory and mitochondria-restoring actions, we engineered BMSCs-derived exosomes (Met-Exo) via metformin pretreatment, which were enriched with miRNAs targeting mitochondrial function, osteogenesis, and inflammation. Specifically, Met-Exo reprogrammed mitochondrial dysfunction of BMSCs under high glucose by restoring mitochondrial dynamics, scavenging reactive oxygen species (ROS), and improving energy metabolism, thereby enhancing osteogenic differentiation. Concurrently, Met-Exo induced macrophage polarization towards an anti-inflammatory M2 phenotype. This approach disrupted the vicious cycle of inflammatory microenvironment (“soil”) and mitochondrial dysfunction in BMSCs (“seeds”), offering a coordinated strategy that targets both the inflammatory milieu and dysfunctional cells. Met-Exo was then incorporated with a copper metal-organic framework into polycaprolactone (PCL) electrospun scaffolds, which provided sustained release of both Met-Exo and pro-angiogenic Cu²⁺ ions. In a rat model of diabetic bone defect, the scaffold significantly improved the inflammatory microenvironment and enhanced vascularized bone regeneration. This study demonstrates that the multifunctional scaffold, combining immunomodulatory and mitochondrially-reprogramming exosomes with a pro-angiogenic component, effectively overcomes the multifaceted barriers in diabetic fractures healing via “immune microenvironment-mitochondrial function-bone formation” temporal therapy, offering a “soil-seed” coordinated intervention for regenerative medicine.
Tendinopathy is a prevalent degenerative musculoskeletal disorder that can progress to heterotopic ossification (HO), ultimately resulting in tissue stiffening and biomechanical deterioration. However, effective early-stage therapeutic strategies to prevent pathological ossification remain limited. In this study, taking advantage of clinical sequencing and preliminary in vivo results that uncovered an early osteoclast-driven target in tendon HO, we engineered a multifunctional zwitterionic nanogel entrapping siponimod (T-S/A nanogel@siponimod) for the potent and selective blockade of osteoclast maturation. The nanogel was prepared by copolymerization of sulfobetaine methacrylate (SBMA) and acrylic acid (AA), and subsequently conjugated to an anti-type I collagen antibody. This design endowed the nanogel with tendon-specific targeting, resistance to nonspecific protein adsorption, and pH-responsive drug release under acidic conditions. In vitro experiments and transcriptomic analyses showed that targeted siponimod delivery markedly inhibited RANKL-induced osteoclastogenesis via blockade of the NF-κB signaling pathway. This intracellular inhibition acted crucially by downregulating the clastokine growth differentiation factor 3 (GDF3), which in turn dampened the pro-osteogenic secretome and abolished the aberrant osteoclast-tendon stem progenitor cell (TSPC) crosstalk. In vivo evaluation in a rat model of tendinopathy-induced HO identified the initial 4 weeks after injury as a critical therapeutic window. Early administration of T-S/A nanogel@siponimod effectively inhibited heterotopic bone formation, reduced the volume of mineralized tissue, and maintained a better-organized tendon tissue structure. Collectively, this study presents a highly specific nanotherapeutic strategy that prevents tendon HO by silencing early osteoclast-driven remodeling. This targeted strategy offers a promising approach for treating local microenvironment-driven musculoskeletal diseases.
Piezocatalytic process presents an effective alternative to photocatalysis for antibacterial treatment due to their degradation efficiency and tissue penetration; however, the necessity for a non-centrosymmetric structure and the prevalence of lead-based materials poses challenges. Therefore, it is essential to develop lead-free and highly efficient piezocatalytic materials to effectively kill bacteria. Herein, we propose a doping engineering design approach to achieve piezoelectric effect and improve the ROS quantum yield by introducing iron hard ferromagnetic element into spinel-phase zinc stannate (Zn2SnO4, ZTO) host matrix. Notably, a 5
Programmed cell death protein-1 (PD-1) and its ligands PD-L1 and PD-L2 form a central inhibitory axis that regulates immune tolerance and plays a key role in tumor immune evasion. Therapeutic blockade of this pathway with monoclonal antibodies has transformed cancer immunotherapy; however, clinical challenges such as limited tumor penetration, immune-related adverse events, high production costs, and resistance mechanisms highlight the need for next-generation PD-1/PD-L1 inhibitors. Nanobodies, single-domain antigen-binding fragments derived from camelid heavy-chain antibodies, have emerged as promising alternatives due to their small size, high stability, strong affinity, excellent tissue penetration, and ease of genetic engineering. Here, we review the structural and expression features of PD-1 and its ligands, as well as their molecular and biochemical roles in shaping tumor immunity. We then provide a comprehensive overview of current PD-1/PD-L1-targeting approaches, including antibodies, small molecules, aptamers, siRNAs, and peptides and compare their therapeutic potential. We highlight recent advances in the development and use of anti-PD-1/PD-L1 nanobodies for cancer diagnosis, modulation of the tumor microenvironment (TME), immune-cell reprogramming, targeted drug delivery, CAR-T cell engineering, and cancer vaccine design. Additionally, we discuss innovative bispecific nanobody constructs that simultaneously target immune checkpoints, remodel the TME, or act as T-cell engagers to boost antitumor immunity. Finally, we address current limitations and translational challenges in nanobody-based therapies and outline future directions to improve their clinical effectiveness. Overall, emerging evidence supports nanobody-mediated PD-1/PD-L1 blockade as a highly versatile and potent platform that could revolutionize next-generation cancer immunotherapy.
Gastric cancer remains a significant global health threat, with mortality largely driven by drug resistance and peritoneal metastasis. Aroyl diheterocyclic pyrroles (ARDHEPs) are potent inhibitors of microtubule assembly but suffer from poor water solubility and limited bioavailability, restricting their therapeutic application. In this study, we developed poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with ARDHEP (ARDHEP@PLGA) to overcome these pharmacological barriers. Our results, derived from both patient-derived human gastric cancer organoids and in vivo xenograft models, demonstrate that ARDHEP@PLGA significantly suppresses tumor growth, induces G0/G1 phase cell cycle arrest, and downregulates mitochondrial function. High-throughput ATAC-seq revealed that ARDHEP@PLGA markedly alters the landscape of chromatin accessibility within gastric cancer cells. Specifically, the treatment promotes the transcriptional activation of the transcription factor zinc finger protein 320 (ZNF320), as evidenced by increased trimethylated H3 lysine 4 (H3K4me3) binding at its promoter region. This epigenetic reprogramming subsequently triggers the activation of the cytokine–cytokine receptor interaction signaling pathway, leading to the significant upregulation of key inflammatory and tumor-suppressive molecules, including IFNAR2, LTA, and IL9, at both the mRNA and protein levels. These findings indicate that ARDHEP@PLGA nanoparticles exert their therapeutic effects by modulating chromatin accessibility to activate the ZNF320-mediated cytokine pathway. This study provides a novel nanotherapeutic strategy for gastric cancer treatment and highlights a specific epigenetic target for future intervention.
Recent advances in targeted alpha therapy have highlighted a central but still unresolved nanobiotechnology problem, namely how to control the fate of recoil daughters after alpha decay. After alpha decay, recoil daughters may escape from the carrier and redistribute to non-target tissues, thereby reducing therapeutic selectivity and confounding absorbed-dose estimation. This challenge places nanomaterials at the center of current development, because their architecture, composition, and surface chemistry can directly determine nanoscale confinement, local recapture, degradation behavior, and transport across biological barriers. At the same time, the rapid expansion of alpha-emitter research and the emergence of more rigorous translational frameworks make it increasingly necessary to link material design with measurable biological and dosimetric outcomes. This review therefore provides a nanobiotechnology-oriented synthesis of recoil physics, daughter redistribution, and engineering strategies for daughter control, with the aim of clarifying how nanomaterial design can improve retention, tumor delivery, and organ sparing in next-generation targeted alpha therapy.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that seriously affects the quality of life in the elderly. The abnormal aggregation of beta-amyloid (Aβ) is a critical driving factor of AD. Tobacco contains various active molecules with neuroprotective effects, which influence the aggregation of Aβ and demonstrate potential for AD treatment in clinical data analysis. Plant-derived extracellular vesicles carry bioactive molecules from their parental cells and exhibit unique advantages in disease therapy due to their natural biocompatibility and low immunogenicity. We isolated extracellular vesicles (tEVs) from tobacco BY-2 cells, detected that they contained abundant components such as proteins, lipids, and metabolites, and proposed that the high levels of HSP70 and pyruvate dehydrogenase enzyme could serve as markers for identifying tEVs. Animal experimental studies showed that tEVs entered the brain via the nasal route and were taken up by astrocytes, reduced the deposition of Aβ plaques in the cortex and hippocampal regions of the brain, decreased the overall Aβ content, and improved the impaired learning and memory abilities of 5xFAD mice. Further studies found that tEVs led to an increase in the phosphorylation expression of PI3K and AKT in astrocytes, upregulated the production of endogenous αB-crystallin protein (Cryab), and reduced the aggregation and content levels of Aβ both within and outside of the cells. These tEV-mediated changes were reversed by pre-treatment with the PI3K/AKT signaling pathway inhibitor LY294002. These findings indicate that tEVs promote the degradation of Aβ by astrocytes via the PI3K/AKT signaling pathway and exert anti-AD effects. tEVs are a promising anti-AD therapeutic drug.
Tumor heterogeneity and an immunosuppressive microenvironment are major obstacles to effective cancer immunotherapy. Personalized nanovaccines derived from autologous tumor cells offer a compelling strategy to overcome these challenges by preserving the full spectrum of patient-specific neoantigens without requiring individual identification of neoantigens. This review systematically categorizes four major platforms: tumor cell lysate-based nanovaccines, tumor cell membrane-coated nanoparticles (NPs), tumor-derived extracellular vesicles (EVs), and in situ nanovaccines. We discuss advanced bioengineering strategies that enhance antigen presentation through valency control, nanoscale spatial patterning, and shape-dependent lymph node trafficking. We further highlight artificial intelligence as an enabling design pillar for neoantigen prioritization, NP formulation optimization, stimuli-responsive carrier design, and patient stratification. Specific nanovaccine platforms, including self-emulsifying, self-aggregating, logic-gated, and nanorobot systems, are highlighted, along with key mechanisms for reshaping the tumor microenvironment (TME), such as physical barrier disruption, metabolic reprogramming, and modulation of critical signaling pathways. The induction of ICD and its variants, pyroptosis, ferroptosis, and cuproptosis, has also been explored as an in-situ vaccination strategy. While no autologous tumor cell-derived nanovaccine has yet received FDA approval, the clinical success of personalized mRNA vaccines (BNT122, mRNA-4157, LK101), a KRAS neoantigen bacterial membrane nanovaccine, the erythrocyte–anti-PD1 conjugate (αPD1-Ery), the TNBC-MERIT study with six-year relapse-free survival (10 out of 14), and methotrexate-loaded tumor-derived exosome nanovaccines for cholangiocarcinoma provides a regulatory roadmap. Preclinical platforms, including PLGA/R848-based M1 macrophage membrane nanovaccines, are advancing toward clinical applications. Despite challenges in manufacturing standardization, off-target autoimmunity, and long-term regulatory safety, autologous tumor cell-derived nanovaccines represent a promising paradigm for potentially durable tumor-specific immunity, particularly for preventing postoperative recurrence and metastasis in high-risk cancer patients.
Micro/nano-topographical cues are potent regulators of cellular behavior and function. However, conventional fabrication techniques (e.g., photolithography, nanoimprinting) rely on complex exogenous processing that often induces surface energy loss and impairs biological signal transduction efficiency. Herein, we report a controllable endogenous topographical construction strategy leveraging strain-induced crystalline phase transition in poly(lactide-glycolide-ε-caprolactone) (PLGCL) to spontaneously engineer surface topography. We demonstrate that anisotropic microgrooves-generated via stretch-induced crystal transformation within a critical dimensional range-exert decisive control over bone marrow stromal cell (BMSC) osteogenic differentiation. Mechanistically, an optimal topographical window was identified wherein groove dimensions promote integrin clustering via contact guidance, driving focal adhesion maturation, actomyosin contraction, RhoA/ROCK pathway activation, and YAP nuclear translocation. This cascade enhances BMSC osteogenic differentiation efficiency. Notably, the engineered topography induced heterogeneity within the stem cell population: the early recruitment driven by SDF-1α synergized with the microgroove mediated osteogenic differentiation in the mid to late stage, while mechanical signals dependent on surface curvature/orientation led to differences in differentiation, thereby contributing to stem cell regulation and bone repair. Concomitantly, the film’s rapid early-phase release gradient of SDF-1α effectively recruits endogenous BMSCs to the defect site, replenishing the stem cell pool for repair. In a rat calvarial cranial defect model, SDF-1α-functionalized films exhibited superior regenerative outcomes. Collectively, this work establishes an endogenous topographical construction paradigm, where stretch-induced microgrooves act as physical-mechanical cues instructing stem cell differentiation. Synergizing with chemical cues, this strategy enables precise, cell-free therapeutic repair, offering a new perspective for designing regenerative materials.
PANoptosis, an inflammatory programmed cell death modality that combines features of pyroptosis, apoptosis, and necroptosis, can significantly enhance tumor immunogenicity. However, its therapeutic application is hindered by challenges such as inefficient reactive oxygen species (ROS) generation, uncontrolled metal ion release, and the immunosuppressive tumor microenvironment (TME). Herein, we construct an ultrasound (US)-activated TME-responsive defect-rich ZnMo-layered double hydroxide (DR-ZnMo-LDH) nanosheets for PANoptosis-mediated sonodynamic immunotherapy. The DR-ZnMo-LDH nanosheets exhibit markedly enhanced US-triggered ROS generation as well as responsive Zn2+ release under both acidic TME and US irradiation. After modification with polyethylene glycol (PEG), in vitro assays demonstrate that DR-ZnMo-LDH-PEG simultaneously induces mitochondrial dysfunction and endoplasmic reticulum stress, leading to robust PANoptosis and immunogenic cell death. In vivo assays indicate that DR-ZnMo-LDH-PEG combined with US irradiation effectively remodels the immunosuppressive TME, elicits a systemic anti-tumor immune response, and significantly suppresses both primary and distant tumor growth, achieving inhibition rates of 96.5
Solid tumor immunotherapy is often constrained by CD8⁺ T cell exhaustion, destabilized immunological synapse formation, and aberrant PD-1 activation; however, the underlying epigenetic transcriptional regulation and actionable targets remain incompletely defined. Therefore, we developed the CD8⁺ T cell membrane-coated GSK3β inhibitor-loaded cerium oxide (CeO₂) nanozyme (CD8m-CeO₂@GSK3i) to enable immunological synapse-targeted delivery of a GSK3β inhibitor and thereby remodel the function of exhausted CD8⁺ T cells. The nano-system was evaluated through characterization, multi-enzyme activity assays, and reactive oxygen species (ROS)-responsive drug-release testing, and was further investigated using mitochondrial metabolism profiling, live-cell imaging, flow cytometry, confocal microscopy, single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq), RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR), and co-immunoprecipitation (Co-IP), before in vivo efficacy was evaluated in B16F10 and MC38 mouse models. The nano-system restored mitochondrial metabolism, Ca²⁺ signaling, and immunological synapse architecture and enhanced CD8⁺ T cell killing and secretory functions. Treatment also reduced PD-1 transcription, attenuated exhaustion-related phenotypes, and altered the GSK3β-TIPE-β-catenin-PD-1 regulatory axis. Combining the nano-system with PD-1 blockade further strengthened antitumor effects. Collectively, this work establishes a nano-intervention strategy for improving immunotherapy responses in solid tumors.
The impermeability of the blood–brain barrier (BBB), formed by a monolayer of endothelial cells, remains a major obstacle for delivering chemotherapeutic drugs to the brain. Ultra-small nanoparticles, particularly nanoclusters smaller than 2 nm, offer a promising strategy to overcome this challenge. Here, we investigate the anti-cancer efficacy and underlying mechanisms of two sizes of platinum-based nanoparticles; platinum nanoclusters (PtNCs: 2 nm) and platinum nanoparticles (PtNPs: 10 nm), synthesized using bovine serum albumin (BSA) as a stabilizer. In this study, PtNCs and PtNPs were tested against paediatric glioblastoma (p-GBM) cells, and were shown to induce cell death, prevent cell migration, and cause cell reproductive death. The mechanism of action of the PtNCs and PtNPs was investigated and compared with cisplatin by examining oxidative stress status, DNA damage, cell cycle arrest, and cell apoptosis. PtNCs exhibited promising catalytic ability under acidic conditions and physiological temperature. They showed the ability to generate free radicals to induce oxidative stress in p-GBM cells, thus causing DNA double strand breaks and G2/M phase cell cycle arrest. Conversely, PtNPs induced S phase cell cycle arrest by causing DNA crosslinking. These findings demonstrate that the cell death mechanism of Pt-based nanoparticles is critically size-dependent. This construct therefore has the potential for an improved anti-cancer treatment for paediatric glioblastoma with negligible cytotoxicity towards the normal organs. It is suggested that PtNCs could provide a promising treatment for p-GBM, and an alternative to conventional platinum-based drugs.
Diabetic wound infections remain highly refractory to treatment due to persistent bacterial colonization, oxidative stress, dysregulated inflammation, vascular insufficiency, and impaired extracellular-matrix remodeling. Current therapeutic strategies remain limited by poor tissue penetration, inadequate infection control, and ineffective inflammatory-oxidative microenvironment modulation. Here, we engineered a sonosensitive antimicrobial peptide composite hydrogel, FFRK8@ZnO2@fHAMA, by integrating human host-defense-peptide-derived FFRK8, microenvironment-responsive ZnO2 microspheres, and fish-collagen-modified hyaluronic acid methacrylate (fHAMA) into an injectable bioactive matrix. Upon low-intensity pulsed ultrasound (LIPUS) irradiation, this hydrogel acts as a multifunctional regenerative dressing that couple broad-spectrum bacterial eradication with oxidative-stress attenuation, macrophage repolarization, angiogenic activation and extracellular-matrix reconstruction. Distinct from conventional passive dressings or antibiotic-dependent therapies, FFRK8@ZnO2@fHAMA enables non-invasive and spatiotemporally precise activation, sustained local therapeutic retention and coordinated immune-redox-metabolic microenvironment remodeling while maintaining favorable biosafety. This sonosensitive peptide hydrogel offers a powerful bioactive strategy for repairing infected diabetic wound and may inspire next-generation therapeutic modality for chronic non-healing tissue regeneration.
Diabetes mellitus severely impairs bone regeneration due to a compromised neurovascular microenvironment. Current therapeutic approaches frequently overlook the need to support neurovascular repair under hyperglycemic conditions, leading to suboptimal bone defect healing. To address these challenges, we developed a low-temperature deposition modeling (LDM)-printed magnesium-containing scaffold incorporating alpha-lipoic acid-encapsulated ethosomes (ALA-Eth), termed the LMA scaffold. In this design, the hierarchical porous structure provided a framework for tissue ingrowth, while magnesium ions and ALA-Eth were introduced to endow the scaffold with the capacity to support vascular and neural repair. In vitro assessments demonstrated that the scaffold enhanced the neurotrophic activity of Schwann cells (SCs) and improved the angiogenic function of endothelial cells under hyperglycemic conditions. Furthermore, osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) was facilitated not only by conditioned medium from scaffold-treated SCs and endothelial cells, but also by the direct osteoinductive activity of the composite scaffold. In vivo implantation in diabetic rat femoral condyle defects revealed that the scaffold promoted neurovascularized bone regeneration. Transcriptomic and cellular analyses further indicated that this regenerative profile was associated with neural, vascular and osteogenic pathways, alongside redox regulation and bioenergetic processes. Collectively, these findings support the potential of the LMA scaffold as a multifunctional biomaterial strategy for neurovascularized bone regeneration under diabetic conditions.
Pancreatic cancer shows limited immune cell infiltration and suboptimal responses to immunotherapy. Notably, dihydrolipoamide S-acetyltransferase (DLAT), a lipoylated mitochondrial protein and key component of the cuproptosis pathway, is highly expressed in pancreatic cancer and positively correlates with PD-L1 levels, supporting a therapeutic strategy that links cuproptosis induction with immune activation. However, most copper ionophores have a short circulating half-life and limited tumor specificity, which reduces copper accumulation in tumor cells and weakens cuproptosis induction. To address these limitations, we developed a bacterial membrane-based, dual-targeted nanosystem (IMPD-L1nb/KAA@ES-Cu NPs) for coordinated delivery of elesclomol–copper (ES-Cu) complex. This platform presents a neutralizing PD-L1 nanobody and a pancreatic tissue-homing peptide (KAA) on bacterial cytoplasmic membranes, enabling increased tumor-specific copper accumulation. The nanosystem enhances cuproptosis-mediated tumor suppression and antigen release, while the membrane-anchored PD-L1 nanobody counters ES-Cu-induced PD-L1 upregulation and blocks immune evasion. Acting as an immunostimulatory agonist, the nanoparticles remodel the immunosuppressive microenvironment by promoting dendritic cell maturation, driving M1 macrophage polarization, and recruiting immune effector cells, including natural killer cells. These effects enhance lymph node trafficking and antigen presentation, ultimately strengthening T cell-mediated tumor eradication. Overall, this nanoplatform couples immunogenic cell death with immune activation, advancing the therapeutic application of cuproptosis in cancer.
Chronic diabetic wounds heal poorly due to persistent hyperglycemia, recurrent infection, and dysregulated inflammation, while their complex microenvironment poses major therapeutic challenges. Yet, therapeutic strategies that actively modulate the wound microenvironment for microenvironment-responsive treatment remain largely underexplored. Here, we engineered a biomimetic multi-enzyme nanozyme and integrated it into an adaptive PBEG@GelMA hydrogel microneedle system to convert excessive glucose into an endogenous substrate for antibacterial therapy. This system establishes a glucose-responsive and pH-dependent catalytic strategy featuring coordinated POD-, CAT-, and SOD-like activities, enabling integrated regulation of glucose levels, bacterial infection, oxidative stress, and wound microenvironment. Mechanistically, (i) glucose oxidase (GOx) senses hyperglycemia, consumes glucose, and generates gluconic acid and H2O2, depriving bacteria of nutrients while priming POD-like catalysis; (ii) under acidic conditions, dissociation of GOx exposes positively charged PB@EPL, which binds to negatively charged bacterial surfaces and enhances POD-like activity to convert H2O2 into highly reactive ·OH, efficiently eliminating bacteria and biofilms with a bactericidal rate above 99.56
Gemcitabine remains the standard chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC); however, its efficacy is limited by poor tumor targeting and low permeability caused by the dense fibrotic stroma. To overcome these limitations, we developed an integrated dual-axis combinatorial strategy. We first constructed biomimetic cancer cell membrane-coated gemcitabine nanoparticles (CMG) and co-administered them with the vitamin D analogue calcipotriol (CAL). Both in vitro and in vivo studies demonstrated that PDAC cells preferentially internalized CMG via clathrin-mediated endocytosis, and CMG can enable sustained intratumoral drug release. Simultaneously, CAL activated the vitamin D receptor signaling pathway in cancer-associated fibroblasts (CAFs), modulatied the expression of fibrosis-related markers, and promoted CAFs to normal fibroblast then potentially enhancing nanoparticle penetration and therapeutic potential. Furthermore, mRNA sequencing, network pharmacology, and bioinformatic analyses comparing wild-type and gemcitabine-resistant PDAC cell lines identified the potential regulatory molecules implicated in CAL-improved chemoresistance, which were validated by structural dynamics and functional assays. In vivo, the CMG/CAL combined therapy significantly inhibited tumor growth while enhancing therapeutic efficiency. This integrated treatment approach rationally couples improved drug delivery with stromal remodeling, offering a promising avenue to overcome chemoresistance in PDAC.
