Synergistic photodynamic and chemodynamic therapy using hypoxia-adaptive Ce6@Co nanoparticles for enhanced tumor suppression

Conventional photodynamic therapy (PDT) is less effective in solid tumors owing to Type-II PDT mechanism's reliance on oxygen (O₂), which is scarce in hypoxic environments. Most hydrophobic photosensitizers have poor water solubility, complicating their formulation and delivery. To address these challenges, Ce6@Co nanoparticles (a hypoxia-adaptive nanoplatform) were developed via coordinating Co²⁺ ions with chlorin e6 (Ce6), exhibiting uniform size (∼230 nm), enhanced dispersibility, and colloidal stability. These nanoparticles generate dual-mode reactive oxygen species (ROS): Type-II ¹O₂ via PDT under 670 nm irradiation and oxygen-independent hydroxyl radical (⋅OH) via Co²⁺-mediated Fenton-like reactions. In vitro, Ce6@Co nanoparticles demonstrated superior cellular uptake and robust ROS amplification, and reduced squamous cell carcinoma (SCC7) cell viability to 34.4 % under normoxia and 20.48 % under hypoxia via synergistic photodynamic and chemodynamic (PDT-CDT) effects, causing considerable apoptosis. In vivo, intratumoral administration of Ce6@Co nanoparticles via laser irradiation completely suppressed tumors in SCC7 tumor-bearing mice. This effect was attributed to favorable intratumoral distribution, enhanced retention, and synergistic PDT-CDT. No systemic toxicity was observed, as indicated by stable body weight, normal serum biomarkers, and unchanged organ histology. The Co²⁺-coordinated photosensitizer system uses hypoxia-elevated H₂O₂ to sustain CDT, effectively overcoming conventional PDT's oxygen dependence and offering a safe and effective dual-modal therapeutic strategy for hypoxic solid tumors.