Jul 2026· Colloids and Surfaces B: Biointerfaces· Vol 268 Pt 1, pp.
116030
· 0 citations· 40 references
Medicine
TL;DR
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.
Abstract
Chemoresistance remains a major obstacle in bladder cancer therapy, driven by the interplay among P-glycoprotein (P-gp)-mediated drug efflux, mitochondrial metabolic reprogramming, and impaired apoptotic signaling. Here, we present a TME-responsive nanoplatform (DR@MPDA@M) composed of MPDA core shielded by manganese dioxide (MnO2) shell, enabling sequential co-delivery of doxorubicin and resveratrol for chemo-/chemodynamic/photothermal therapy. The MnO2 layer selectively degrades under the acidic and glutathione-rich TME, enabling controlled drug release while simultaneously generating Mn2+ that catalyze Fenton-like reactions to produce cytotoxic hydroxyl radicals (•OH). Notably, this design strategically targets the mitochondria-P-gp axis that resveratrol potently downregulates P-gp expression to suppress drug efflux, while the Mn2+-induced oxidative stress disrupts mitochondrial function, depleting intracellular ATP and inhibiting heat shock protein 90. The resultant energy crisis synergistically impairs P-gp-mediated efflux and sensitizes cancer cells to doxorubicin-induced apoptosis. Upon 808 nm laser irradiation, the MPDA core mediates photothermal conversion, further accelerating the Fenton-like reaction and potentiating chemotherapy. Both in vitro and in vivo bladder tumor models demonstrate that DR@MPDA@M achieves favourable tumor inhibition. This work provides a mitochondria-P-gp axis-targeted strategy that integrates chemo-/chemodynamic/photothermal therapy, offering a promising paradigm for overcoming chemoresistance in bladder cancer.
INTRODUCTION
Strategic harnessing and modulation of the tumor microenvironment (TME) can overcome its inherent therapeutic barriers and enhance treatment efficacy. TME hallmarks, including hypoxia, excessive glutathione (GSH), and insufficient H2O2, severely limit reactive oxygen species (ROS)-based therapies.
METHODS
To address this issue, leveraging the high lactate level in TME, we developed BIMLM (BSA-IR780-MnO2@LOX@Membrane) as a biomimetic nanoplatform integrating lactate oxidase (LOX)-driven lactate exhaustion with MnO2-coated IR-780 for TME remodeling and self-amplifying ROS generation. BIMLM was fabricated by first preparing MnO2-coated IR-780 nanoparticles, then immobilizing LOX, and finally cloaking them with tumor cell membranes. After BIMLM accumulates selectively within tumor tissue, intratumoral excess lactate triggers the sequential therapeutic cascades. Specifically, LOX-catalyzed lactate oxidation generates H2O2 to induce metabolic starvation by disrupting energy supply. This H2O2 is then decomposed by MnO2 to produce O2, which simultaneously facilitates cyclic lactate oxidation and enhances photodynamic therapy (PDT). The resulting Mn2+ further triggers a Fenton-like reaction, converting the self-supplied H2O2 into •OH and thereby amplifying chemodynamic therapy (CDT). Concurrently, GSH depletion increases cellular susceptibility to ROS, further potentiating both PDT and CDT. Notably, coordinated GSH downregulation and ROS upregulation synergistically trigger ferroptosis, which combines with apoptosis to achieve potent tumor suppression.
RESULTS
Taken together, the nanoplatform reconfigures the TME through lactate depletion, H2O2 elevation, hypoxia alleviation, and GSH scavenging. This series of changes creates a self-amplifying cycle that enhances PDT/CDT efficacy while triggering metabolic starvation and ferroptosis, which collectively enable tumor eradication. This strategy establishes a promising paradigm for high-efficiency tumor therapy.
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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.
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Triple-negative breast cancer (TNBC) remains a formidable challenge due to its aggressive progression and the absence of established therapeutic targets. This study engineered a multifunctional, tumor microenvironment (TME)-responsive nanoplatform MnO2@Man/DOX, which was designed for synergistic targeted chemotherapy and TME modulation. The platform comprises a manganese dioxide (MnO2) core for redox regulation and a mannose (Man) shell for active targeting and metabolic sensitization, stabilized with bovine serum albumin and sodium dodecyl sulfate. MnO2@Man/DOX nanoparticles are nearly spherical (289 nm) and exhibit dual-responsiveness by efficiently depleting intracellular glutathione and catalyzing endogenous hydrogen peroxide into cytotoxic hydroxyl radicals via Fenton-like reactions. In vitro, the nanoplatform demonstrated a remarkable 8-fold reduction in IC50 (0.52 μg/mL) compared with free doxorubicin (4.2 μg/mL) in 4 T1 cells. Transcriptomic analysis suggested that MnO2@Man/DOX is associated with TNF signaling and apoptosis-related pathways, including extrinsic, intrinsic, and endoplasmic reticulum stress-mediated programs. In vivo evaluations in 4 T1 tumor-bearing mice confirmed preferential tumor accumulation and superior growth inhibition with a high biosafety profile, including a hemolysis rate below 5% and minimal systemic toxicity. By integrating receptor-mediated targeting, redox homeostasis disruption, and chemosensitization, MnO2@Man/DOX offers a promising metabolism-oriented strategy for treating refractory TNBC.
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