Tumor-specific activated polymeric nanotuners disrupt positive feedback cycle of hypoxia and apoptosis evasion for potent cancer radiotherapy

Effective cancer radiotherapy is usually hindered by the self-perpetuating feedback cycle between tumor hypoxia and apoptosis evasion. Herein, a tumor-specific activated polymeric nanotuner is developed to boost radiotherapy outcomes by disrupting this vicious cycle. The designed nanotuner is composed of a proapoptotic peptide-engineered catalase core and a pH-detachable polymer shell. They can maintain the core-shell structure to against immune clearance and enzymatic degradation under the "turn-off" state. When reaching the tumor site, the nanotuners hold acid-responsive "turn-on" property by dissociating the polymeric shell, facilitating the tumor accumulation and cellular internalization of the exposed functional core. Subsequently, the internalized core of polymeric nanotuners efficiently decomposes endogenous hydrogen peroxide (H₂O₂) into oxygen (O₂) for hypoxia alleviation, thus upregulating the expression of proapoptotic protein Smac. Furthermore, the apoptotic-inducing peptide modified on the core surface further boosts the Smac-induced apoptosis signal, intervening in tumor apoptosis evasion and ultimately realizing the efficient radiotherapeutic efficiency by blocking this vicious cycle. In vivo studies demonstrated that treatment with polymeric nanotuners remarkably enhances radiation-mediated tumor ablation without perceptible side effects. This study sheds light on the innovative attempt to specifically interfere with the feedback cycle in tumor radioresistance, pioneering the way for achieving safe and efficient cancer therapies.