Targeted drug delivery remains pivotal for enhancing therapeutic efficacy in cancer treatment. While nanomedicines harness the enhanced permeability and retention (EPR) effect for passive tumor accumulation, their efficacy is often hindered by physiological barriers that limit optimal delivery. Active delivery strategies by immune cell (neutrophils etc.) hitchhiking offer a promising approach to surmount these obstacles; however, attenuated tumor-associated inflammation restricts their tumor-directed migration. Here, we present a biomimetic nanoplatform based on polydopamine nanoparticles coated with bacterial outer membrane vesicles (OMV@PDA). Upon single injection, these nanoparticles not only passively accumulate in tumors via the EPR effect and generate localized hyperthermia under near-infrared irradiation to ablate tumor cells and trigger inflammation, but also leverage their pathogen-mimicking coating to promote efficient uptake by circulating neutrophils (83.2% phagocytosis rate). The photothermally amplified inflammation broadcasts "find-me" signals to recruit nanoparticle-laden neutrophils to tumor sites. Consequently, a single injection orchestrates EPR effect and neutrophil hitchhiking for spatiotemporal accumulation, achieving high-intensity and sustained tumor accumulation. Notably, this strategy yielded an remarkable tumor inhibition rate of 95%, underscoring superior therapeutic efficacy. Our findings establish a self-reinforcing paradigm for advancing targeted drug delivery in oncology.

Osteoporosis (OP) is characterized by impaired bone formation, largely attributed to dysfunctional osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Circulating factors, particularly exosomes acting as natural nanocarriers, play crucial roles in regulating BMSCs function within the bone microenvironment. However, the specific mechanisms by which serum exosomes contribute to osteogenic impairment in OP remain elusive. Serum exosomes were isolated from ovariectomized (OVX) rats and characterized. Their impact on BMSCs osteogenesis was evaluated. Global miRNA sequencing identified dysregulated miRNAs in OVX-derived exosomes. The roles of miR-29a-3p and miR-29c-3p were investigated using gain- and loss-of-function approaches in vitro and in vivo. Bioinformatic analysis and experimental validation identified Ten-Eleven Translocation 3 (TET3) as a direct target. TET3 deficiency was modeled in OVX mice. Transcriptomic analysis, bisulfite sequencing PCR, and chromatin immunoprecipitation sequencing were employed to delineate the mechanism of action of TET3. Exosomes derived from OVX rat serum significantly inhibited osteogenic differentiation of BMSCs. MiRNA sequencing revealed a pronounced downregulation of miR-29a-3p and miR-29c-3p within these exosomes. Functionally, overexpression of miR-29a/29c-3p rescued bone formation defects both in vitro and in vivo, while their inhibition suppressed osteogenesis. Mechanistically, TET3, a key DNA demethylase, was confirmed as a direct target of miR-29a/29c-3p. Crucially, TET3 deficiency in OVX mice stimulated BMSCs osteogenesis and bone remodeling. Further mechanistic dissection demonstrated that TET3 represses osteogenesis by directly increasing DNA methylation at the Sox9 promoter, thereby suppressing Sox9 expression, and concurrently inhibiting the PI3K/AKT signaling pathway. Our study defines a novel exosome-mediated pathway in OP: Deficiency of serum exosome-delivered miR-29a/29c-3p elevates TET3, which epigenetically represses Sox9 via promoter hypermethylation and inhibits PI3K/AKT signaling. This exosome/miR-29/TET3/Sox9 axis unveils promising therapeutic targets for OP intervention, particularly leveraging exosome-based modulation or epigenetic editing.

Hepatocellular carcinoma (HCC) remains a major global health challenge, with limited therapeutic efficacy and poor prognosis. To address chemoresistance and immunosuppression in HCC, we developed a lactate-modulating multifunctional prodrug nanocomposite (GD-A NPs). This system is self-assembled from a pentavalent arsenate prodrug (AsO₄³⁻), the hydrogen sulfide (H₂S) donor GYY4137, and the lactate export inhibitor diclofenac (DCF), enabling precise responsiveness to the acidic and reductive tumor microenvironment. Endogenous H₂S selectively reduces intracellular As⁵⁺ to highly cytotoxic As³⁺ in the acidic tumor milieu, thereby activating the prodrug while minimizing systemic toxicity. Simultaneously, H₂S enhances tumor glycolysis-derived lactate production, which, in combination with DCF-mediated inhibition of lactate efflux, leads to intracellular acidification and reversal of the immunosuppressive microenvironment. Excessive lactate accumulation disrupts endoplasmic reticulum (ER) homeostasis, where SERCA2 inhibition depletes ER Ca²⁺ stores and triggers GRP78 dissociation. This event activates PERK-mediated eIF2α phosphorylation and the downstream ATF4/CHOP pathway, ultimately inducing immunogenic cell death (ICD) and promoting systemic immune activation. This is evidenced by the release of damage-associated molecular patterns (DAMPs), dendritic cell maturation, and T cell activation. By integrating lactate metabolism regulation, prodrug activation, and immune remodeling, this strategy provides a promising avenue for combined chemo-immunotherapy of HCC.

The active ingredients of Traditional Chinese Medicine with diverse structures exhibited anti-inflammatory and lipid lowering functions, demonstrating significant therapeutic effects in inflammatory diseases of atherosclerosis. We incorporate Astaxanthin (AST) and Dihydroartemisinin (DHA) into PLGA NPs to synthesized HA@PLGA@AST/DHA NPs (HPAD NPs) for alleviating atherosclerosis. In vitro assay indicated that the designed HPAD NPs promoted cholesterol efflux of macrophages by enhancing selective lipophagy, which is benefit to lipid antigen degradation. Meanwhile, HPAD NPs regulated T-cell differentiation and crucially induced macrophages from pro-inflammatory M1 type to anti-inflammatory M2 type. In vivo study demonstrated that HPAD NPs decreased the necrotic core dimension and improved plaque stability in ApoE mice with atherosclerosis. Overall, this research indicated the promise of HPAD NPs for the targeted therapy of atherosclerosis.

Traditional hyperthermia-boosted photothermal therapy (PTT) for infected wounds often suffers from thermal damage to healthy tissue, exacerbates immune dysregulation, and compromises antibacterial efficacy in deep tissue. Here, we developed a functional microneedle system (MTF@MNs) by incorporating MXene-tannic acid/iron (MXene-TA/Fe, MTF) nanosheets into a photocrosslinkable GelMA/PEGDA hydrogel matrix. The engineered microneedle architecture facilitates targeted delivery of therapeutic nanosheets into deep, biofilm-rich subcutaneous regions, which are characterized by elevated HO levels, acidic pH, and poor drug permeability. Under mild near-infrared (NIR) irradiation, MTF@MNs synergistically enhance the peroxidase-like nanozyme activity of MXene-TA/Fe while accelerating Fe/Fe release, facilitating efficient eradication of deep-tissue infections without thermal injury. Our results demonstrate that MTF@MNs not only exhibit robust reactive oxygen species (ROS) scavenging capacity, but also promote macrophage polarization toward pro-regenerative phenotypes. Furthermore, they attenuate pro-inflammatory cytokine release by inhibiting the TNF/MAPK signaling pathway in macrophages. Collectively, the MTF@MNs system accelerates infected wound healing through reprogramming the immune microenvironment, enhancing collagen deposition, and stimulating angiogenesis, thus offering a promising strategy for the management of deep-tissue infections.

Quantitative, label-free monitoring of dynamic cell adhesion remains challenging. Meta-Surface Plasmon Resonance Microscopy (Meta-SPRM) is a novel platform integrating bright-field microscopy with engineered Meta-SPR nanocup arrays. This system simultaneously acquires bright-field images and Meta-SPRM signals, enabling their computational separation and co-analysis to provide multifaceted insights into cell-substrate interactions. Meta-SPRM offers sensitive, high-throughput, and long-term label-free quantification of cell adhesion strength and distribution. It captures dynamic processes like cell spreading and migration at micrometer lateral resolution. Notably, Meta-SPRM signals spatially correlate with key focal adhesion proteins (Integrin-β1, Vinculin), and an intrinsic intracellular signal polarity correlates with cell migration direction. Meta-SPRM provides a powerful, label-free tool for dynamic cell adhesion studies, overcoming limitations of traditional methods.

Atherosclerosis is a chronic inflammatory disease affecting arterial walls and remains a leading cause of morbidity and mortality worldwide. While anti-inflammatory therapy is widely recognized as a critical component in the management of atherosclerosis, current treatments are often limited by adverse effects and suboptimal efficacy. Membrane-derived nanovesicles have demonstrated excellent biocompatibility and prolonged circulation times, making them effective drug delivery carriers. However, their targeting capabilities remain limited, as only a small fraction of transmembrane proteins possesses intrinsic targeting functions. To overcome these limitations and leverage the targeting capability of folate in inflammatory disease, we designed biomimetic nanovesicles modified with folate by covalently conjugating folate-C-PEG-NHS to nanovesicles under physiological conditions enabling efficient drug delivery to atherosclerotic plaques. Meanwhile we also identified the PU.1 inhibitor DB1976 as an anti-inflammatory target for the treatment of atherosclerosis. Mechanistically, DB1976 suppresses inflammation by inhibiting the IL-1β/NF-κB signaling pathway, reducing reactive oxygen species (ROS) levels, and decreasing apoptosis rates. Folate-modified biomimetic nanovesicles loaded with DB1976 achieved promising therapeutic outcomes. In summary, folate-modified macrophage biomimetic nanovesicles loaded with a PU.1 inhibitor effectively alleviate atherosclerosis by targeting inflammation in atherosclerotic plaques, highlighting their potential as a promising therapeutic strategy for atherosclerosis treatment.

Renal tubular epithelial cells (TECs), which are highly susceptible to injury during acute kidney injury (AKI), have notable regenerative effects on renal recovery after AKI. AKI-driven metabolic reprogramming of TECs plays a critical role in determining whether kidneys recover functionally or develop fibrosis. Targeting the metabolism of TECs offers valuable insights into AKI treatment. Growth hormone-releasing hormone (GHRH) and its analog GHRH peptide (GHRP) play beneficial roles in the field of regenerative medicine. Here, we designed a self-assembling GHRP-6 peptide hydrogel, and we hypothesized that this hydrogel could reprogram the metabolism of TECs, further enhancing recovery from AKI. Metabolomic sequencing analysis revealed that spermidine, L-glutamine, and acetyl-CoA, which are involved in amino acid and fatty acid metabolism, were highly enriched in a mouse model of AKI treated with the GHRP-6 hydrogel. Further study revealed that GHRP-6 hydrogel treatment enhanced the survival of TECs in the ischemic microenvironment by activating the mTOR-P70 pathway. In conclusion, GHRP-6 hydrogel treatment has beneficial therapeutic effects on AKI through the targeting of metabolic reprogramming, which offers a novel therapeutic strategy to protect TECs in AKI treatment.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, with early diagnosis critical for improving outcomes. Current diagnostic tools, including serum biomarkers and imaging techniques, exhibit limited sensitivity and specificity. Although extracellular vesicles (EVs) have emerged as a promising source of cancer biomarkers, their clinical utility is hampered by inefficient enrichment technologies.To overcome this limitation, a microfluidic platform was developed to enable rapid and efficient EV capture.

In this study, we prepared chemically crosslinked silk fibroin (SF) and sodium alginate (Alg) biomimetic scaffolds reinforced with bioceramic nanohydroxyapatite (nHAp) for bone tissue engineering (BTE) applications. The pore sizes of these scaffolds were effectively controlled by varying the composition of the SF/nHAp/Alg biocomposites. The scaffold prepared with a 40:20:40 SF: nHAp: Alg ratio exhibited excellent swelling properties, reaching over 1700% within 70 min. In vitro degradation studies demonstrated that these biomimetic scaffolds exhibited controlled degradation, taking over 30 days to achieve 50% degradation. The scaffolds also showed good mechanical properties; they maintained structural integrity and did not break, even under a load approximately 800 times their own weight. Additionally, scaffolds loaded with synthetic peptide salmon calcitonin effectively controlled initial burst release and enabled sustained therapeutics delivery for up to two weeks. The biocompatibility of the scaffolds was evaluated using in vitro cell viability and hemolysis assays, which revealed good safety for human dermal fibroblast cells and negligible toxicity to rabbit red blood cells. Importantly, the scaffolds promoted cell proliferation and alkaline phosphatase secretion in human bone marrow stem cells. Histological and immunological analyses in a scaffold-implanted mouse model have demonstrated biocompatibility, supporting osteoclastic resorption and osteoblastic mineralization by downregulating RANKL. Furthermore, the chick chorioallantoic membrane assay showed the excellent angiogenic properties of the scaffold. These results suggest that the bioceramic-reinforced SF/Alg biomimetic scaffold has significant potential for use in BTE.

Nucleic acid nanotechnology (NAN) has emerged as a powerful platform for constructing programmable molecular architectures, with broad applications spanning biomedicine, materials science, and molecular computing. While numerous reviews have covered the design principles and functional modalities of enzyme-free NAN systems, a comprehensive framework for understanding enzyme-involved NAN remains conspicuously absent. Given the growing interest in enzyme-involved systems, enzymes offer distinct advantages to NAN, including enhanced programmability, dynamic control, and expanded functional versatility. This review addresses that gap by systematically categorizing the enzymatic toolkit-including polymerases, modifying enzymes, endo-/exonucleases, ligases, other protein-based enzymes, as well as nucleic acid enzymes such as DNAzymes, ribozymes, and XNAzymes-and elucidating their roles in enabling structural assembly and dynamic control at the molecular level. Enzymes function not only as assembly agents for nucleic acid nanostructures, facilitating strand extension, ligation, cleavage, and chemical modification, but also as essential driver tools mediating degradation, release, and template-guided polymerization. Their integration has led to highly adaptive and reconfigurable systems with capabilities far surpassing enzyme-free counterparts. We further highlight key advances in enzyme-powered NAN across diverse frontiers, including in vitro diagnostics (IVD), cellular and in vivo imaging, DNA data storage and computing, biomimetic material synthesis, and drug delivery. By mapping catalytic mechanisms to functional outputs, and identifying current bottlenecks in specificity, modularity, and integration, this review establishes a unified conceptual foundation and design roadmap for the next generation of enzyme-driven nucleic acid nanodevices.

The combination of chemotherapy and immune checkpoint blockade therapy shows great potential in tumor treatment, but their integration remains a great challenge. Herein, hypoxia-responsive prodrugs integrating paclitaxel (PTX) and bromodomain-containing protein 4 inhibitor JQ1 were designed and fabricated into nanoparticles (DJNP NPs) in the presence of DSPE-PEG. After accumulation at the tumor site, DJNP NPs can respond to tumor hypoxic condition and trigger the release of PTX and JQ1. The released PTX can result in cell apoptosis, which further evokes immunogenic cell death to boost the intratumoral infiltration of cytotoxic T lymphocytes. Meanwhile‌, overexpression of programmed cell death ligand 1 (PD-L1) is suppressed by JQ1, thereby reversing PD-L1-mediated immune resistance to synergistically promote adaptive antitumor immune response. This hypoxia-sensitive versatile nanoplatform provides an elegant paradigm for precise tumor therapy.

The mechanism of sepsis related liver injury (SRLI) is unclear and its treatment method is unsatisfactory. The aim of this study was to investigate the effects of BRCC3 on SRIL and preparation of kupffer cells membrane encapsulated ZIF-8 loaded BRCC3 siRNA (K-EVs@ZIF-8@siRNA) to target BRCC3 to treatment of SRLI. Liver tissues from control mice and SRLI mice were used for RNA sequencing for searching differential genes. The cercal ligation and punchure (CLP) model and lipopolysaccharide (LPS) model were used to evaluate the mechanisms of BRCC3 and the effects of K-EVs@ZIF-8@siRNA on SRLI. The results of RNA-Seq showed BRCC3 and NLRP1were significantly increased in Kuepfer cells of liver tissues of SRLI mice. BRCC3 and NLRP1 have co-localization in Kuepfer cells. It was also found that knock out BRCC3 had protective effects on SRLI via deubiquitylation modification of NLRP1 to inhibit of NLRP1. K-EVs@ZIF-8@siRNA was successfully prepared in this study and exhibited the characteristics of nanoparticles. K-EVs@ZIF-8@siRNA could be enriched in liver tissues and also be absorbed by Kuepfer cells. K-EVs@ZIF-8@siRNA significantly alleviated SRLI by inhibition the BRCC3/NLRP1 signaling pathway. In conclusion, BRCC3 as a key marker was identified in SRLI and K-EVs@ZIF-8@siRNA was successfully prepared for treating SRLI. This study provides a new target and treatment for SRLI.

Concurrent chemoradiotherapy (CRT) combined with PD-1/PD-L1 targeting immunotherapy (IM) has emerged as a promising treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, individual responses to this treatment vary, highlighting the need for predictive biomarkers to improve therapeutic efficacy. Interleukin-15 (IL-15) has shown potential in enhancing anti-tumor immunity, but its role in ESCC remains poorly defined.

The abuse of antibiotics has accelerated the emergence of multidrug-resistant (MDR) bacterial strains, while the development of novel antibiotics has failed to keep pace with the evolution of bacteria. Consequently, there is an urgent need to develop innovative alternative antibacterial materials to combat drug-resistant bacterial infections. Herein, we fabricate Cu-doped hollow Ca-tannic acid nanoparticles (ATA@Cu NPs) with pH-sensitive drug release behavior to effectively eliminate MDR bacteria at acidic infection sites. Under a pH 6.0 environment that simulates the infection microenvironment, the ATA@Cu NPs can release the Cu to potently eradicate methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Pseudomonas aeruginosa (MRPA). Notably, owing to the excellent intracellular drug delivery property, ATA@Cu NPs exhibit potent bactericidal efficiency against intracellular bacteria. Furthermore, the ATA@Cu NPs demonstrate commendable therapeutic performance in treating MRPA-infected keratitis, as they significantly alleviate the bacterial burden by diminishing 4.0 logs of MRPA, promote the recovery, and restore normal corneal structure. Additionally, using a self-made nebulization device, the ATA@Cu NPs display robust therapeutic efficiency in combating MRSA-induced pneumonia and eliminating intracellular MRSA with a 2.8 log reduction via pulmonary delivery. Therefore, this study fabricates pH-responsive Cu-doped hollow Ca-polyphenol nano-therapeutics to combat MDR bacteria-induced infection, thereby providing a potential therapeutic strategy to address the challenges of MDR bacteria in the future.

Radiotherapy (RT) is a primary modality in clinical cancer treatment. However, its ability to induce tumor cell apoptosis offers limited activation of anti-tumor immunity. Pyroptosis, characterized by cell swelling, membrane rupture, and the release of pro-inflammatory cytokines, has been demonstrated to potentiate immune responses against cancer cells. Herein, we develop hollow spiky manganese oxide (HSpiM) nanocarriers to enhance RT-induced tumor pyroptosis and elicit anti-tumor immune responses. The spiked structure of HSpiM nanocarriers promotes intracellular lysosomal rupture, while simultaneously producing elevated amounts of reactive oxygen species (ROS) after RT, to synergistically activate the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome. Notably, lysosomal rupture-induced autophagy inhibition amplifies NLRP3-mediated pyroptosis by blocking lysosome-mediated degradation pathways. Moreover, we encapsulate an ESCRT inhibitor, the Ca chelator BAPTA-AM, into HSpiM nanocarriers (designated as BA@HSpiM) to promote tumor pyroptosis by disrupting the repair of damaged cell membranes. RT-induced pyroptosis elicits potent anti-tumor immunity, effectively suppressing tumor metastasis and generating durable immune memory to reject tumor rechallenge. Overall, inducing tumor pyroptosis presents a promising strategy to enhance the efficacy of RT, as it improves the outcomes of local treatment and activates systemic anti-tumor immune responses.

The efficacy of antitumor immunotherapy is closely associated with the expansion of tumor-infiltrating CD8 T cells. However, within the tumor microenvironment, CD8 T cells often exhibit reduced proliferation due to persistent exposure to tumor antigens. The cytokine IL-2 is a potent growth factor that can drive the expansion of tumor-infiltrating lymphocytes. While its clinical application has been severely limited by systemic toxicity and in vivo instability. To address these challenges, we have developed a dual-responsive system (EcN@UCNP/Gel-CTX) leveraging the hypoxic tropisms of E. coli Nissle 1917(EcN). This system is capable of producing IL-2 in situ upon near-infrared (NIR) irradiation and releasing low-dose cyclophosphamide (CTX) in response to matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment. The EcN@UCNP/Gel-CTX system not only drives the expansion of CD8 T cells and boost the activity of NK cells but also reduces Treg cell populations, thereby remodeling the immune microenvironment and eliciting robust tumor-specific immune responses in H22 subcutaneous tumors in mice and confers long-term protection against tumor rechallenge by promoting the generation of durable memory T cells. Our findings provide an both light and tumor microenvironment responsive platform for enhanced cancer immunotherapy.

With the continuous discovery of new materials and a deeper understanding of tumor diseases, more possibilities have been identified for the delivery of antitumor drugs and the treatment of tumors. Currently, the treatment of tumors is not limited to traditional chemotherapy and radiotherapy. Photothermal therapy (PTT) is a new type of noninvasive therapeutic strategy that has aroused widespread concern. PTT can generate a large amount of heat in a specific external environment to achieve the purpose of tumor ablation. Notably, PTT produces heat to kill tumors. In addition, tumor tissues produce many related molecules, which can submit antigens to stimulate T cells and cause antitumor immunity, a process known as the immunogenic cell death (ICD) effect of the tumor environment. However, relying solely on PTT to induce the ICD effect in tumor tissues is challenging, and the immunosuppressive character of the tumor microenvironment weakens the curative effect. Therefore, it is necessary to combine therapy with PTT to achieve the desired efficacy. Here, this review summarizes recent nanomaterial-based PTT and its concomitant ICD, discusses how to amplify the effect of ICD and combines immunotherapy with cotherapy to carry out antitumor research, and finally looks forward to the prospect of PTT combination therapy for tumor treatment.

Excessive inflammation, infection, persistent reactive oxygen species (ROS) accumulation, hyperglycemia, and vascular lesions in diabetic chronic wounds severely impair healing. Currently, there is no treatment regimen available to improve the complex microenvironment of such wounds. We have designed a comprehensive microenvironment intervention system, namely the composite dressing CVCeCG. The injectability, self-healing properties, and tissue adhesion of hydrogel make it an ideal physical barrier. The CVCeCG hydrogel incorporates a photothermal therapy (PTT) strategy, enabling photothermal activation of a missile-like bactericidal program to eliminate infections rapidly. Additionally, CVCeCG hydrogel remodels the immune microenvironment, constructs a dynamic regulatory network of epidermal/dermal cells, macrophages, and blood vessels through immune training and metabolic reprogramming. Even after the dressing is removed, it can still promote wound healing and has long-term effects. Furthermore, this hydrogel dressing alleviates wound hypoxia and reduces ROS levels, thereby further mitigating inflammation and promoting tissue repair. In the diabetic rat model with MRSA-infected wounds, the CVCeCG hydrogel significantly eliminated infection, reduced local inflammatory responses and ROS levels, and established a mutually supportive cycle between improved immune microenvironment and angiogenesis, thereby promoting wound healing. In summary, this work provides significant insights into the use of photothermal therapy to eliminate bacteria and improve the immune microenvironment through immune training and metabolic reprogramming, offering new strategies for comprehensively improving the microenvironment of chronic wounds in diabetes. A hydrogel (CMC-PDA/GEL) was created by combining gelatin (GEL) with catechol-modified carboxymethyl cellulose (CMC-DA). Composite hydrogel dressings in CVCeCG were created by adding polycaprolactone microspheres loaded with calcium peroxide (CPO@PCL) or vancomycin (Van@PCL) and cerium oxide nanoparticles (CeNPs) to CMC-PDA/GEL. This hydrogel can mimic missiles to eliminate infections quickly, remodel the local immune microenvironment by training the immune system and metabolic reprogramming, and clear ROS, establishing a comprehensive microenvironment intervention system, which helps wounds heal.

Radioresistance and off-target toxicity remain major challenges in prostate cancer (PCa) radiotherapy. Here, we report a biomimetic nanoplatform (Au/MOF-FIN@M-gy1) that synergistically enhances radiation deposition and ferroptosis for precision radiosensitization. By engineering macrophage membranes with prostate-specific membrane antigen (PSMA)-targeting nanobodies (gy1), we achieve tumor-selective delivery of Au/MOF nanoparticles preloaded with ferroptosis inducers (FINs). Upon lysosomal release, FINs disrupt redox homeostasis via GPX4 suppression, while Au/MOF amplifies radiation-induced reactive oxygen species (ROS), collectively triggering lethal lipid peroxidation cascades. This dual mechanism is further demonstrated to elicit radiosensitizing effects in both bone-metastatic and radio-refractory PCa models without requiring radiation dose escalation, thereby improving the therapeutic index. Our study demonstrates a nanoparticle-enabled strategy to enhance tumor-specific radiotherapy by dual-targeting metabolic vulnerabilities.