A synergistic cascade nanoreactor breaks bladder cancer chemoresistance: Synergizing cholesterol metabolism reprogramming with cGAS-STING-mediated metallotherapy
Aug 2026· Materials Today Bio· Vol 40, pp. 103537· 0 citations· 55 references
Medicine
TL;DR
A folate-targeted zeolitic imidazolate framework-67 (ZIF67)-based nanoreactor termed CCZF, co-loaded with cholesterol 25-hydroxylase (CH25H) and cisplatin, to orchestrate a metabolism-chemo-immunity cascade with mutually amplifying components, providing a promising multifaceted strategy for treating chemo-resistant bladder cancer.
Abstract
Bladder cancer chemoresistance arises from a self-reinforcing vicious cycle of aberrant cholesterol metabolism and immunosuppression, which conventional single-target therapies fail to disrupt. Here, we report a folate-targeted zeolitic imidazolate framework-67 (ZIF67)-based nanoreactor termed CCZF, co-loaded with cholesterol 25-hydroxylase (CH25H) and cisplatin, to orchestrate a metabolism-chemo-immunity cascade with mutually amplifying components. First, the intrinsic catalase (CAT)-like activity of ZIF67 generates oxygen in situ to fuel CH25H-mediated cholesterol depletion that reaches 72% in resistant bladder cancer cells. This process disrupts lipid raft structure and downregulates P-glycoprotein (P-gp), resulting in 97.2% cisplatin retention in resistant cells. Second, enhanced cisplatin cytotoxicity induces nucleocytoplasmic translocation of high-mobility group box 1 (HMGB1), an early molecular signature associated with immunogenic cell death (ICD). Third, Co2+ released from degraded ZIF67 activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. The CH25H-derived metabolite 25-hydroxycholesterol (25HC) acts as an immunomodulatory oxysterol that works with high-mobility group box 1 (HMGB1) to potentiate toll-like receptor 4 (TLR4)-associated innate immune signaling and remodel the immunosuppressive tumor microenvironment. In MB49R tumor-bearing mice, intratumoral CD8+ T cell infiltration increases by 2.3-fold on day 14 after treatment. In preclinical bladder cancer models, this tripartite synergy achieves 95.9% short-term tumor growth suppression with no obvious systemic toxicity under the tested dosage and observation period, providing a promising multifaceted strategy for treating chemo-resistant bladder cancer.
A TME-responsive nanoplatform composed of MPDA core shielded by manganese dioxide (MnO2) shell, enabling sequential co-delivery of doxorubicin and resveratrol for chemo-/chemodynamic/photothermal therapy, offering a promising paradigm for overcoming chemoresistance in bladder cancer.
Zhihua Zeng, Chao Hu, Yihe Li et al.· Colloids and Surfaces B: Bio...· 0 citations
Hypoxia in the tumor microenvironment (TME) is a hallmark of solid tumors and is tightly associated with the development of chemoresistance and immunosuppression, severely compromising the efficacy of mainstream clinical oncological treatments. Platinum‐based metallodrugs, especially oxaliplatin (Oxa), serve as first‐line chemotherapeutics in clinical practice. However, their clinical utility is greatly restricted by acquired drug resistance, insufficient tumor accumulation, and weak immunostimulatory capacity. Herein, we synthesize a platinum–ruthenium nanohybrid prodrug (denoted as PR) via self‐assembly, which integrates Oxa PR and ruthenium ions for synergistic chemo‐/chemodynamic‐/immunotherapy of hypoxic tumors. The PR nanohybrid possesses intrinsic multi‐enzyme activities (catalase, peroxidase, and glutathione peroxidase), enabling efficient oxygen generation, hydroxyl radical production, and glutathione depletion. These cascading events enhance chemosensitivity, trigger robust immunogenic cell death, and activate the cGAS‐STING signaling pathway. Furthermore, nanocatalytic modulation of the hypoxic TME alleviates hypoxia‐driven immunosuppression, downregulates PD‐L1 expression on cancer cells, and reinforces antitumor immune responses. In vitro and in vivo investigations demonstrate that PR nanohybrid exhibits superior anticancer efficacy over free Oxa and displays promising potential in combination with PD‐1 blockade therapy. These findings highlight the PR nanohybrid as a versatile TME‐modulating platform for hypoxic tumor treatment, offering a novel strategy to advance platinum‐based combination cancer therapy.
Huixi Yi, Yue Zheng, Nannan Fu et al.· Advanced Healthcare Material...· 0 citations
Combining this CuZnS@BSA nanoregulator with PD-L1 blockade led to potent suppression of both subcutaneous tumor growth and lung metastasis, thus providing a direct, elegant link between metabolic reprogramming and systemic immune activation for TNBC therapy.
Jingyi Yang, Qi Li, Pi Zhao et al.· Theranostics· 0 citations
Ovarian cancer remains difficult to treat due to the persistence of chemoresistant cancer stem-like cells (CSCs), which are major drivers of tumor relapse. Herein, we engineered a hyaluronic acid-functionalized nanoplatform (HS-Cu@DOX) via the assembly of a shikonin–copper (SKN-Cu) coordination complex with hyaluronic acid, followed by electrostatic loading of doxorubicin (DOX), enabling tumor-targeted co-delivery of both therapeutic agents. This nanoplatform disrupts intracellular redox homeostasis to induce cuproptosis while concurrently suppressing CSC stemness through downregulation of key pluripotency-associated transcription factors (e.g., SOX2, OCT4, and NANOG). By depleting intracellular glutathione (GSH) and impairing antioxidant defenses, HS-Cu@DOX disrupts the oxidative stress resilience of CSCs, thereby restoring their sensitivity to DOX-induced apoptosis. Consequently, this strategy enhances DOX-mediated cytotoxicity and reduces systemic toxicity while maintaining potent antitumor efficacy. Collectively, our findings demonstrate that combining cuproptosis induction with CSC stemness suppression represents a promising strategy for overcoming chemoresistance, highlighting HS-Cu@DOX as a potential therapeutic candidate for recurrent ovarian cancer.
Shanshan Liu, Yichun Huang, Fanchen Yan et al.· Materials Today Bio· 0 citations
Triple-negative breast cancer (TNBC) is associated with rapid progression and poor sensitivity to monotherapies, necessitating combination strategies to enhance tumor immunogenicity, reprogram the tumor microenvironment (TME), and convert immunologically "cold" tumors into "hot" ones. In this study, we develop a pH-responsive, pyroptosis-inducing nanoreactor, ZnS/ZIF-90:Fe/Vk3 (ZZFV), designed to elicit potent antitumor immunity. Under acidic conditions, ZZFV rapidly degrades, releasing Zn2+, Fe2+, H2S, and Vk3. H2S promotes glucose uptake and consumption while downregulating cytochrome c oxidase subunit IV (COX IV) expression, whereas Zn2+ suppresses lactate dehydrogenase (LDH) activity, collectively disrupting glucose metabolism and exacerbating intracellular acidification. Meanwhile, NAD(P)H quinone oxidoreductase 1 (NQO1), highly expressed in tumor cells, catalyzes the conversion of Vk3 to H2O2, which is subsequently converted to highly toxic •OH through Fe2+-mediated Fenton reactions. Additionally, Zn2+ and H2S synergistically disrupt mitochondrial function, thereby amplifying reactive oxygen species (ROS) production. Excessive ROS triggers Caspase-1-dependent pyroptosis, leading to the liberation of damage-associated molecular patterns. These events promote dendritic cell (DC) maturation, robust T-cell activation, M1 macrophage polarization, and expansion of central memory T-cell populations, thereby conferring durable immune protection. Consequently, ZZFV demonstrates potent antitumor efficacy, effectively overcoming immune tolerance in TNBC and achieving robust, sustained antitumor immunity.
Wenjia Liu, Ying Wang, Xiangyu Hao et al.· Journal of Nanobiotechnology· 0 citations
Osteosarcoma (OS), the most common primary bone malignancy in adolescents, faces limited treatment options and high chemoresistance rates. Hydrogen sulfide (H2S), an endogenously produced gaseous signaling molecule that regulates cellular redox homeostasis, promotes chemoresistance in multiple cancers, but its role in osteosarcoma remains unclear. Here, we identify endogenous H2S as a key driver of cisplatin resistance in osteosarcoma and develop a novel H2S-targeting theranostic platform named bismuth-based metal-organic nanocapsule network (Bi-MONC). The nanocapsule exhibits excellent drug-loading capacity. During circulation, Bi-MONC undergoes gradual size reduction and disassembly into smaller particles while remaining as discrete nanoparticles until it reaches the osteosarcoma site. Furthermore, Bi-MONC binds intracellular H2S to form Bi2S3, enabling in situ photoacoustic imaging of tumors while triggering ferroptosis via endoplasmic reticulum stress and ubiquitin-mediated proteasomal degradation of GPX4, enhancing cisplatin efficacy. This dual-action material overcomes enzymatic redundancy in H2S production, offering a universal approach to scavenge intracellular H2S. Collectively, our study presents an innovative strategy that simultaneously addresses the challenges of precise diagnosis and chemoresistance in osteosarcoma.
Yixuan Lin, Kai Yuan, Yihao Liu et al.· Bioactive Materials· 0 citations
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