This nanoplatform integrates CPT chemotherapy, selenium intervention, and the p53 mutation background into a single system, establishing a toxicity-controlled, efficacy-enhanced strategy and reveals how selenium-based nanomaterials remodel redox homeostasis, bypass p53 deficiency, and reprogram apoptotic networks.
Abstract
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.
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
Rationale Since the therapeutic resistance of triple-negative breast cancer (TNBC) is mainly attributable to excessive glutathione (GSH) accumulation and its ‘cold’ immune landscape, we designed biomimetic CuZnS@BSA nanoregulators that exploit a pH-triggered ‘disarm-and-attack’ cascade, thereby initiating a well-defined, sequential therapeutic process in the acidic tumor microenvironment. Methods Biomimetic CuZnS@BSA nanoclusters were synthesized via a self-assembly method. Their pH-responsive release kinetics and synergistic therapeutic mechanisms (GSH depletion, ROS generation, and cuproptosis) were systematically evaluated in vitro using 4T1 cells. In vivo anti-tumor efficacy, immune microenvironment remodeling, and anti-metastatic effects were investigated in subcutaneous and lung metastasis TNBC mouse models, both alone and in combination with PD-L1 blockade. Results The platform first releases H2S to deplete intracellular GSH, thus removing the major antioxidant defenses of the tumor, then follows with the release of Cu2+ to induce cuproptosis, which effectively bypasses the apoptosis resistance commonly seen in TNBC. In addition, the released Zn2+ acts as an immune modulator by promoting the recognition of leaked mitochondrial DNA. This activates the cGAS-STING signaling pathway, and in vivo experiments clearly showed that it remodels the tumor microenvironment in a highly favorable manner, characterized by increased CD8+ T cell infiltration and enhanced dendritic cell maturation. Conclusion Combining this 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
By integrating receptor-mediated targeting, redox homeostasis disruption, and chemosensitization, MnO2@Man/DOX offers a promising metabolism-oriented strategy for treating refractory TNBC.
Guanghui Mei, Hanwen Wang, Xinhua Lin et al.· Nanomedicine: Nanotechnology...· 0 citations
Triple-negative breast cancer (TNBC) lacks effective tumor-selective strategies, particularly limiting ferroptosis-based therapies that depend on oxidative stress. Here, we develop a structurally reinforced ternary redox-cycling nanoreactor that integrates Zr4⁺-stabilized zeolitic imidazolate framework-8 (ZIF-8) with redox-active Cu/Mn centers and ultrasmall Au nanodots, while co-loading paclitaxel (PTX) for acidic tumor microenvironment-responsive release. The Cu-Mn-Au interfaces enable rapid electron shuttling, sustaining multivalent metal cycling, accelerating Fenton-like reactive oxygen species (ROS) generation, depleting GSH, and promoting lipid peroxidation. Density functional theory (DFT) calculations further support its self-perpetuating redox mechanism. Dual surface modification with 4 T1 cell membranes and folic acid confers homotypic and receptor-mediated targeting. Mechanistic studies reveal coordinated GPX4/SLC7A11 suppression, PTX-enhanced cell-cycle arrest, and NCOA4/HO-1-mediated ferritinophagy, collectively amplifying ferroptosis. Unlike conventional metal-organic frameworks (MOFs), this Zr-reinforced trimetallic system maintains continuous redox cycling under reductive conditions. Overall, the nanoreactor achieves sustained ROS amplification, iron-homeostasis remodeling, and enhanced tumor-selective ferroptosis, offering a promising therapeutic strategy for TNBC.
Wanmei Zhou, Zixin Wang, Chengdong Nie et al.· International journal of pha...· 0 citations
This innovative nanoplatform combines active targeting, stimuli-responsive drug release, and chemo-chemodynamic therapy (CCDT), presenting a promising approach to overcome drug resistance and improve the treatment of OSCC.
Zhiliang Nie, Q. Jiang, Xiwen Wan et al.· RSC Advances· 0 citations
It is established that S-MnC is a potent, dual-action therapeutic agent that mediates both apoptosis and ferroptosis, offering a promising strategy to overcome drug resistance in aggressive, metastatic cancers and to enhance therapeutic efficacy.
Aswathy Anil, Diksha Tripathi, S. Nayak et al.· Archives of Biochemistry and...· 0 citations