Biodegradable CoSnO3 nanozymes modulate pH-responsive graphene quantum dot release for synergistic chemo-sonodynamic-nanocatalytic cancer therapy

Albeit nanozymes are widely applied for nanocatalytic therapy (NCT), the unsatisfactory catalytic activity of nanozymes accompanied by complex tumor microenvironment (TME) greatly pose a barrier to the therapeutic effect of NCT. Moreover, developing a high-efficiency nanozyme with biodegradability is still a huge challenge, which hinders their further clinical translation. Herein, pH-responsive biodegradable CoSnO3 nanocubes are synthesized and employed as sonosensitizers and nanozymes due to their narrow bandgaps (1.6 eV) and Co2+/Sn4+-mediated multi-enzyme activities. After depositing the graphene quantum dot (GQD) topoisomerase inhibitors on CoSnO3 nanocubes, the heterojunction-fabricated GQD/CoSnO3 shows cascaded amplification of ROS generation, which is ascribed to the inhibition of electron-hole pair recombination, Co2+-mediated peroxidase (POD)-mimic catalytic reaction to generate OH, Co3+/Sn4+-mediated depletion of overexpressed GSH, and catalytic decomposition of endogenous H2O2 for providing more O2 for enhanced SDT. More importantly, GQD/CoSnO3 heterojunctions are slowly degraded in the weakly acidic TME, resulting the tumor-specific release of GQDs after completion of SDT, which could induce DNA damage and cell apoptosis for chemotherapy to further enhanced the antitumor efficacy. The synergetic therapeutic efficacy of GQD/CoSnO3 heterojunctions through chemotherapy, SDT, and NCT could realize “three-in-one” multimodal oncotherapy to completely eliminate tumors without recurrence. This work provides a paradigm of exploring pH-responsive biodegradable nanozymes as a drug carrier to realize tumor-specific drug release for enhanced SDT and NCT.