pPB-Fe3O4@CaO2-BzATP Nanozyme System Synergistically Induces Ferroptosis, Pyroptosis, and Apoptosis in Prostate Cancer

Treating cancers with apoptosis resistance, particularly prostate cancer, remains a significant challenge. While ferroptosis, an iron-dependent non-apoptotic cell death, shows promise, its efficacy is often limited by insufficient hydrogen peroxide (H2O2) supply, which impedes sustained generation of cytotoxic free radicals. Monotherapy approaches frequently yield suboptimal results. Therefore, strategies that enhance H2O2 supply and co-activate multiple cell death pathways are crucial to maximize tumoricidal effects and overcome resistance mechanisms.

Researchers developed a multifunctional targeted nanozyme system, pPB-Fe3O4@CaO2-BzATP, designed for synergistic prostate cancer therapy. The pPB cyclic peptide component endowed the nanozyme with enhanced prostate tumor-specific targeting ability. Upon internalization by tumor cells, calcium peroxide (CaO2) was hydrolyzed under acidic conditions to produce H2O2 and calcium ions (Ca2+). The iron oxide (Fe3O4) nanozyme then catalyzed this self-supplied H2O2 to generate highly cytotoxic ·OH radicals. The system also incorporated 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP) to activate the P2X7 receptor. The therapeutic efficacy and safety were verified through both in vitro and in vivo studies.

The pPB-Fe3O4@CaO2-BzATP nanozyme system demonstrated significant synergistic tumoricidal effects. Upon tumor cell internalization, CaO2 hydrolysis under acidic conditions generated H2O2 and Ca2+. The Fe3O4 nanozyme then catalyzed the self-supplied H2O2 to produce highly cytotoxic ·OH radicals, leading to augmented ferroptosis in prostate cancer cells. Simultaneously, the released Ca2+ triggered calcium overload, which effectively elicited apoptosis. Furthermore, BzATP activated the P2X7 receptor, which not only enhanced Ca2+ influx to further reinforce calcium overload but also promoted potassium ion (K+) efflux. This K+ efflux subsequently led to nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome assembly, ultimately inducing pyroptosis.