Biodegradable Biomimic Copper/Manganese Silicate Nanospheres for Chemodynamic/Photodynamic Synergistic Therapy with Simultaneous Glutathione Depletion and Hypoxia Relief

TLDR

ROS‑involved photodynamic and chemodynamic therapies together promise enhanced anticancer effects. We report biodegradable cancer‑cell‑membrane‑coated mesoporous Cu/Mn silicate nanospheres that target cancer cells and generate ROS via singlet oxygen and GSH‑activated Fenton reaction for synergistic CDT/PDT. The nanospheres decompose tumor H₂O₂ to O₂, generate singlet oxygen under 635‑nm laser, and GSH‑triggered degradation releases Cu⁺ and Mn²⁺ to catalyze Fenton reactions, deplete GSH, and provide MRI contrast, enabling hypoxia relief and ROS‑mediated therapy. The nanospheres exhibit homotypic targeting, relieve hypoxia, deplete GSH, disrupt the tumor microenvironment, and achieve significant in‑vitro and in‑vivo cancer growth inhibition, demonstrating exceptional therapeutic efficacy.

Abstract

The integration of reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhanced anticancer effects. Herein, we report biodegradable cancer cell membrane-coated mesoporous copper/manganese silicate nanospheres (mCMSNs) with homotypic targeting ability to the cancer cell lines and enhanced ROS generation through singlet oxygen (1O2) production and glutathione (GSH)-activated Fenton reaction, showing excellent CDT/PDT synergistic therapeutic effects. We demonstrate that mCMSNs are able to relieve the tumor hypoxia microenvironment by catalytic decomposition of endogenous H2O2 to O2 and further react with O2 to produce toxic 1O2 with a 635 nm laser irradiation. GSH-triggered mCMSNs biodegradation can simultaneously generate Fenton-like Cu+ and Mn2+ ions and deplete GSH for efficient hydroxyl radical (•OH) production. The specific recognition and homotypic targeting ability to the cancer cells were also revealed. Notably, relieving hypoxia and GSH depletion disrupts the tumor microenvironment (TME) and cellular antioxidant defense system, achieving exceptional cancer-targeting therapeutic effects in vitro and in vivo. The cancer cells growth was significantly inhibited. Moreover, the released Mn2+ can also act as an advanced contrast agent for cancer magnetic resonance imaging (MRI). Thus, together with photosensitizers, Fenton agent provider and MRI contrast effects along with the modulating of the TME allow mCMSNs to realize MRI-monitored enhanced CDT/PDT synergistic therapy. It provides a paradigm to rationally design TME-responsive and ROS-involved therapeutic strategies based on a single polymetallic silicate nanomaterial with enhanced anticancer effects.