A self-sufficient nanoreactor orchestrating calcium overload and sonodynamic/chemodynamic-amplified ferroptosis for oral squamous cell carcinoma therapy

Bacteria-derived components hold great promise for cancer therapy owing to their versatile biological properties. We previously reported that Porphyromonas gingivalis cell walls (PgCW), rich in intrinsic µ-oxo bisheme ([Fe(III)PPIX] 2 O), can effectively mediate both sonodynamic therapy (SDT) and chemodynamic therapy (CDT). More recently, we identified PgCW’s inherent potential to trigger ferroptosis. However, its therapeutic efficacy is limited by the hypoxic tumor microenvironment (TME) and insufficient endogenous hydrogen peroxide (H 2 O 2 ) required for catalytic reactions. Herein, a self-sufficient nanoreactor (DCP) was developed by depositing calcium peroxide (CaO 2 ) within dendritic large-pore mesoporous silica nanoparticles (DLMSNs), followed by the electrostatic adsorption of PgCW. Under ultrasound irradiation, DCP combines SDT and CDT with continuous glutathione (GSH) depletion to trigger ferroptosis. In the acidic TME, the decomposition of CaO 2 generates O 2 to enhance PgCW-mediated SDT, supplies H 2 O 2 for Fenton-like CDT, and releases Ca 2+ to induce calcium overload. The abundant reactive oxygen species (ROS) from CaO 2 -supplemented SDT and CDT, together with GSH exhaustion, amplify ferroptosis, driving severe lipid peroxidation (LPO) and cell membrane rupture to release damage-associated molecular patterns (DAMPs) for primary tumor regression. Furthermore, intracellular calcium overload synergistically promotes this ferroptosis-mediated immunogenic cell death (ICD), which, combined with the innate adjuvanticity of PgCW, drives robust systemic immune activation to suppress distant tumors. In summary, this nanoreactor overcomes TME limitations through self-sufficient substrate supply and efficiently combines calcium overload with amplified ferroptosis to suppress the growth and metastasis of oral squamous cell carcinoma (OSCC). These findings suggest a potential strategy for precision cancer immunotherapy.