Protein Corona-Detachable Microwave Ablation Amplifiers Actuate Pyroptosis to Repolarize Immortal Cancer into Senescent Ones

Cancer immortality represents high plasticity and tolerance, and incomplete treatment methods such as microwave ablation (MWA) remodel the residual cancer microenvironment to further potentiate cancer resistance. Nanomedicine is a solution, but the serum protein corona and abnormal intratumoral blood vessels attenuate their delivery efficiency. Herein, protein corona-detachable MWA amplifiers consisting of O₂-binding mesoporous silica nanoparticles and doxorubicin (DOX) have been engineered. Such MWA amplifiers can achieve MWA-triggered O₂ release to assist in detaching the adsorbed protein corona and reoxygenate MWA-aggravated hypoxic tumor to normalize intratumoral blood vessels, respectively, which favor amplifier delivery into tumor, addressing the above two delivery hurdles. Their multiple action mechanisms actuate the nonclassical pyroptosis pathway to activate premature cellular senescence, which dampens inherent and MWA-aggravated cancer stemness, plasticity, and DOX chemoresistance especially after uniting with MWA-aggravated hypoxic microenvironment reversion. Additionally, the above action rationales promote O₂ bubble-mediated inertial cavitation to boost MWA outcome with repressed tumor residues after MWA. Collectively, such MWA amplifiers successfully target protein corona detachment, vascular normalization, cancer immorality repolarization into senescence, pyroptosis activation, and hypoxic microenvironment attenuation, thereby providing more enlightenment and insights into incomplete cancer therapy.