Self-enriching nanozyme with photothermal-cascade amplification for tumor microenvironment-responsive synergistic therapy and enhanced photoacoustic imaging

Achieving precise intratumoral accumulation and coordinated activation remains a major challenge in nanomedicine. Photothermal therapy (PTT) provides spatiotemporal control, yet its efficacy is hindered by heterogeneous distribution and limited synergy with other modalities. Here, we develop a dual-activation nanoplatform (IrO x -P) that integrates exogenous photothermal stimulation with endogenous tumor microenvironment (TME)-responsive catalysis for synergistic chemodynamic therapy (CDT) and ferroptosis induction. The IrO x core exhibits robust peroxidase- and catalase-like activities, enabling Ir 3+ /Ir 4+ redox cycling for glutathione depletion, hydroxyl radical generation and O 2 production. Surface conjugation of P-selectin targeting peptides directs selective binding to activated platelets. Upon mild PTT, vascular injury induces platelet activation, triggering secondary self-enrichment of IrO x -P at tumor sites and amplifying catalytic activity. This cascade enhances CDT/ferroptosis efficacy while enabling O 2 -augmented photoacoustic imaging for real-time monitoring. The strategy establishes a self-recruitment nanotheranostic paradigm that couples PTT-induced biological effects with catalytic nanomedicine, offering a versatile approach for precision cancer therapy. • Photothermal-cascaded nanozyme catalysis amplifies chemodynamic and ferroptosis for synergistic therapy. • Dual-responsive activation strategy achieves integrated spatiotemporal therapeutic coordination. • P-selectin-guided platelet recruitment mechanism enhances tumor-specific nanoparticle enrichment. • H 2 O 2 -triggered O 2 bubble generation boosts photoacoustic imaging via cavitation-enhanced contrast.