TPP-coated Mo-doped W ₁₈ O ₄₉ biodegradable nanomaterials with mitochondria-targeting and pH-responsive properties for synergistic photothermal therapy/chemodynamic therapy/chemotherapy

The primary clinical challenge in antitumor nanodrug therapy lies in overcoming the limited tumor accumulation of nanodrugs due to off-target distribution and achieving precise tumor targeting while minimizing damage to healthy tissues. Herein, we developed a novel multifunctional nanodrug delivery system, TPP-MoWO@DOX@CP, which integrates synergistic photothermal therapy (PTT), chemodynamic therapy (CDT), and chemotherapy with mitochondria-targeting and immune modulation capabilities. The system is based on molybdenum (Mo)-doped W₁₈O₄₉ nanobundles (MoWO NBs), which exhibit exceptional photothermal conversion efficiency (46.66%) under NIR-II (1064 nm) laser irradiation and Fenton-like reactivity for generating cytotoxic hydroxyl radicals (˙OH) from endogenous hydrogen peroxide (H₂O₂). The system shows (1) mitochondria-specific targeting <i>via</i> triphenylphosphine (TPP) functionalization, ensuring precise subcellular localization and enhanced therapeutic efficacy; (2) pH-responsive biodegradability, enabling selective stability in the acidic tumor microenvironment (TME) while promoting rapid degradation in normal tissues to reduce systemic toxicity; and (3) immune modulation through compound polysaccharide (CP) coating, improving biocompatibility and augmenting antitumor immune responses. Under 1064 nm laser irradiation, TPP-MoWO@DOX@CP demonstrated remarkable tumor growth inhibition through the synergistic effects of PTT, CDT, and chemotherapy. Both <i>in vitro</i> and <i>in vivo</i> experiments validated its outstanding photothermal performance, robust ˙OH generation, and biodegradability, showcasing a promising approach for precise cancer therapy with minimal off-target effects. This multifunctional platform addresses critical gaps in current nanomedicine, offering a transformative strategy for clinical translation.