Cisplatin-Doped Black Phosphorus Nanomedicines Overcome Platinum-Based Anticancer Drug Resistance via Piezoelectric-Mediated Adaptive Homeostasis Disruption.
Aug 2026· Advances in Materials· pp.
e23163
· 0 citations· 30 references
Medicine
TL;DR
A DDP-doped black phosphorus (BP) nanomedicine protected by polydopamine coating that synergistically delivered DDP and piezoelectric BP to precisely disrupt resistance homeostasis and thereby reverse DDP resistance is established.
Abstract
The clinical efficacy of platinum-based chemotherapeutics is frequently diminished by the emergence of resistance during prolonged treatment. Cisplatin (DDP)-resistant tumors adapt to chemotherapeutic stress by establishing a new state of adaptive homeostasis that sustains cellular survival under drug pressure, albeit at the expense of high metabolic burden and acquired vulnerability. Exploiting this intrinsic weakness, we designed a DDP-doped black phosphorus (BP) nanomedicine protected by polydopamine coating (DDP-BP@PDA) that synergistically delivered DDP and piezoelectric BP to precisely disrupt resistance homeostasis and thereby reverse DDP resistance. DDP-BP@PDA altered the intracellular uptake pathway of DDP and disrupted the redox balance of resistant cells via piezocatalysis. Concurrently, piezoelectric polarization enhanced the peroxidase-like activity via electron injection, leading to the generation of substantial reactive oxygen species (ROS). This ROS burst compromised the integrity of the endoplasmic reticulum (ER) membrane and exacerbated the protein-folding burden, thereby amplifying ER stress. Mechanism study reveals that excessive ER stress downregulated the expression of DNA repair proteins, making resistant cells highly sensitive to DDP-induced DNA damage. Through these synergistic effects, DDP-BP@PDA disrupted the adaptive homeostasis of DDP-resistant cells, thereby significantly inhibiting the progression of DDP-resistant tumors. This study establishes a promising therapeutic strategy to combat DDP-resistance via piezoelectric-driven disruption of adaptive homeostasis.
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.
Zhihua Zeng, Chao Hu, Yihe Li et al.· Colloids and Surfaces B: Bio...· 0 citations
Selenium deficiency is linked to gastric cancer, and p53 mutant tumors often acquire chemoresistance. To address this, we designed a camptothecin (CPT) dimeric prodrug with a hybrid -S-Se-S- linker (CPT-S-Se-S-CPT). It self-assembles into uniform nanoparticles (SSeSCPT NPs) with dual redox-responsive release triggered by glutathione and reactive oxygen species. Selenium plays dual synergistic roles: it enhances cellular uptake and pharmacokinetics while reducing systemic toxicity; it also acts as a redox-active center to amplify oxidative stress, activating p38/MAPK and unfolded protein response pathways, thereby inducing p53-independent apoptosis and overcoming drug resistance. In vivo, SSeSCPT NPs prolong plasma half-life, achieve efficient tumor accumulation via the EPR effect, and show potent antitumor activity in p53 mutant gastric cancer models. Surface selenium groups recognize Toll-like receptor 4 (TLR4) overexpressed on tumor cells, promoting clathrin/caveolin-mediated endocytosis and bypassing EPR size limitations. This nanoplatform integrates CPT chemotherapy, selenium intervention, and the p53 mutation background into a single system, establishing a toxicity-controlled, efficacy-enhanced strategy. It also reveals how selenium-based nanomaterials remodel redox homeostasis, bypass p53 deficiency, and reprogram apoptotic networks. This work provides mechanistic insights and translational directions for precision therapy of p53 mutant gastrointestinal malignancies.
Cuiman Tang, Zhongjuan Wang, Yankun Liu et al.· ACS Nano· 0 citations
Faced with the growing challenge of antimicrobial resistance, developing non‐antibiotic therapies is imperative. Photodynamic and photothermal therapy (PDT/PTT) are promising due to their minimal side effects and low risk of resistance. However, their efficacy is limited by inadequate reactive oxygen species (ROS) generation, finite photothermal conversion efficiency (PCE), bacterial antioxidant systems, biofilm barriers, and the constraints of single‐modality treatments. To overcome these bottlenecks, this study innovatively co‐assembled the phototherapeutic molecule Y6 with allicin (A) into the Y6A nanoplatform to achieve multi‐mechanism antibacterial activity. Leveraging Y6's strong intramolecular charge transfer (ICT), extended π‐conjugated backbone, and twisted long alkyl chain, Y6A simultaneously achieves efficient ROS generation and 55.2% PCE. Thus, Y6A eradicated up to 99.9% of Methicillin‐resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (P. aeruginosa). This high efficacy is attributed to a synergistic antimicrobial strategy that couples structural disruption and oxidative damage via bimodal phototherapy with allicin‐mediated suppression of biofilm formation and energy metabolism. In an MRSA‐infected wound model, irradiated Y6A accelerated healing by 90%, modulating inflammation and promoting collagen deposition. This work not only confirms the exceptional PDT/PTT efficacy of Y6A against drug‐resistant bacteria but also provides innovative concepts and experimental evidence for the development of synergistic phototherapeutic antibacterial materials.
Yuan Xu, Y. Zhong, Ping Tang et al.· Advanced Healthcare Material...· 0 citations
Abstract Chemodynamic therapy (CDT) eradicates tumor cells by generating hydroxyl radicals (•OH) through Fenton/Fenton-like reactions, yet its therapeutic efficacy is severely constrained by intrinsic deficiencies of the tumor microenvironment (TME), including insufficient endogenous hydrogen peroxide(H2O2), suboptimal pH, robust glutathione (GSH)-mediated reactive oxygen species (ROS) scavenging, and tumor hypoxia. As potent synergistic modalities, photodynamic therapy (PDT) elevates oxidative stress via ROS overproduction, while photothermal therapy (PTT) accelerates Fenton reaction kinetics and improves intratumoral nanotherapeutic penetration, collectively remedying the inherent drawbacks of single CDT. Unlike conventional reviews that primarily catalogue nanomaterial diversity and classification, this review constructs a refined mechanistic framework to elaborate the complementary mechanisms of PDT and PTT toward CDT in terms of reaction kinetics modulation, endogenous substrate replenishment, and tumor antioxidant defense inhibition. We systematically overview the core synergistic principles of integrated nanosystems, covering ROS cascade amplification, GSH depletion-initiated ferroptosis, TME acidification, extracellular matrix (ECM) degradation, and immunogenic cell death. We further summarize recent advances in dual-modal PDT-CDT, PTT-CDT, and PDT-PTT-CDT synergistic nanoplatforms, and highlight the evolutionary trend of such nanotherapeutics-from primitive thermochemical coupling designs to advanced architectures with TME-responsive targeted delivery, second near-infrared (NIR-II) deep-tissue penetration, enzyme-cascaded self-substrate supply, and integrated theranostic functions. Moreover, the key bottlenecks hindering clinical translation are discussed, including limited light penetration depth, TME heterogeneity, suboptimal biosafety profiles, and inadequate clinical validation systems. Three pivotal priorities for future translational development are further proposed: the fabrication of NIR-II deep-penetrating nanoplatforms, the establishment of standardized manufacturing and quality control workflows for regulatory compliance, and the development of TME-adaptive, imaging-guided precision tumor delivery strategies.
Yuxuan Ma, Jie Gong, Zixuan Wu et al.· International Journal of Nan...· 0 citations
Pancreatic cancer responds poorly to conventional chemotherapy, largely because of the pronounced resistance of tumor cells to chemotherapy-induced apoptosis. Ferroptosis, a non-apoptotic form of programmed cell death, has emerged as a promising strategy to overcome this resistance. However, its therapeutic efficacy is often limited by insufficient hydrogen peroxide (H2O2) and excessive glutathione (GSH) in the tumor microenvironment (TME). Herein, we developed a nanoplatform, HM-MnO2@DOX/CaO2@PDA/HA (HMDCPH), using hollow mesoporous manganese dioxide (HM-MnO2) as a carrier to co-deliver doxorubicin (DOX) and calcium peroxide (CaO2). The crosslinked PDA/HA shell enhanced both the tumor-targeting capability and biocompatibility of the nanoplatform. In the TME, HM-MnO2 depleted GSH and promoted reactive oxygen species (ROS) generation, whereas CaO2 decomposition generated H2O2 and released Ca2+, inducing mitochondrial calcium overload and further aggravating oxidative stress. These synergistic effects enhanced lipid peroxidation (LPO) and exacerbated ferroptosis-related oxidative damage. Moreover, the near-infrared (NIR)-triggered photothermal effect further strengthened the antitumor efficacy of HMDCPH. In addition, nanoplatform degradation released Mn2+, enabling T1-weighted magnetic resonance imaging (MRI). Collectively, this study presents a synergistic nanotherapeutic strategy that integrates chemotherapy, photothermal therapy, and ferroptosis-related mechanisms to overcome chemoresistance in pancreatic cancer.
Pan Yang, Shuai He, Mingdong Xu et al.· Materials Today Bio· 0 citations
Chemodynamic therapy (CDT) holds great promise for tumor treatment by catalyzing endogenous hydrogen peroxide (H2O2) into cytotoxic reactive oxygen species (ROS). However, its efficacy is severely compromised by glutathione (GSH)-mediated ROS scavenging and intrinsically slow reaction kinetics. To address these limitations, we developed cerium molybdate-doped polyaniline nanoparticles (MoCe@PANI NPs) to enable a synergistic combination of photothermal therapy (PTT) and CDT, thereby triggering immunogenic cell death (ICD) and enhancing antitumor immunity. Mechanistically, MoCe@PANI NPs deplete intracellular GSH and generate abundant ROS via Ce4+/Mo5+/Mo6+-mediated redox cycles, leading to mitochondrial dysfunction and amplified ferroptosis. Crucially, near-infrared II (NIR-II) laser irradiation induces localized hyperthermia, which simultaneously executes PTT and accelerates the Fenton-like reaction kinetics, further intensifying ferroptotic cell death. This combinatorial strategy effectively activates tumor-associated immune responses, achieving effective ablation of primary tumors and eliciting a systemic abscopal effect that suppresses untreated distant metastases. Collectively, this study presents a robust nanoplatform integrating chemodynamic and photothermal therapies for potent cancer immunotherapy.
Yulin Kuang, Cheng Lu, Bolan Yu et al.· Bioactive Materials· 0 citations