Zinc-Manganese Sulfide Nanoplatform for Tumor-Microenvironment-Responsive Chemodynamic/Gas Therapy and Immunomodulation

Abstract

Chemodynamic therapy (CDT) holds promise for cancer treatment, yet its efficacy is often limited by insufficient hydrogen peroxide (H2O2) supply and the dense extracellular matrix (ECM) in solid tumors. To address these challenges, we developed polyethylene glycol-modified zinc manganese sulfide nanoparticles (ZMSPN) that integrate CDT, gas therapy, and tumor microenvironment modulation within a single pH-responsive platform. Upon reaching the acidic tumor microenvironment, ZMSPN simultaneously releases zinc ions (Zn2+), manganese ions (Mn2+), and hydrogen sulfide (H2S). The released Mn2+ ions generate cytotoxic hydroxyl radicals (·OH) via a Fenton-like reaction, while H2S amplifies this effect by inhibiting catalase (CAT) to preserve endogenous H2O2. Meanwhile, Zn²⁺ ions upregulate matrix metalloproteinase-2 (MMP-2) expression, promoting collagen degradation and enhancing drug penetration. Notably, this coordinated release creates a self-amplifying therapeutic cascade with H2S-enhanced CDT combined with Zn2+ ions-mediated ECM remodeling that distinguishes ZMSPN from conventional platforms. Beyond direct tumor cell killing, ZMSPN treatment induces immunogenic modulation, as evidenced by damage-associated molecular patterns (DAMPs) and enhanced intratumoral T cell infiltration, indicating favorable remodeling of the tumor immune microenvironment. Additionally, the responsive release of Mn2+ ions enables T1-weighted magnetic resonance imaging (MRI) for real-time treatment monitoring. By integrating these synergistic mechanisms, ZMSPN achieves potent antitumor efficacy with multifunctional capabilities in a single nanoplatform.