Dual-enzyme decorated semiconducting polymer nanoagents for second near-infrared photoactivatable ferroptosis-immunotherapy.

Enzymes provide a class of potential options to treat cancer, while the precise regulation of enzyme activities for effective and safe therapeutic actions has been poorly reported. Dual-enzyme decorated semiconducting polymer nanoagents for second near-infrared (NIR-II) photoactivatable ferroptosis-immunotherapy are reported in this study. Such nanoagents (termed SPH GA ) consist of hemoglobin (Hb)-based semiconducting polymer (SP@Hb), adenosine deaminase (ADA) and glucose oxidase (GOx) with loadings in a thermal-responsive nanoparticle shell. NIR-II photoactivation of SPH GA results in the generation of heat to trigger on-demand releases of two enzymes (ADA and GOx) via destroying the thermal-responsive nanoparticle shells. In the tumor microenvironment, GOx oxidizes glucose to form hydrogen peroxide (H 2 O 2 ), which promotes the Fenton reaction of iron in SP@Hb, resulting in an enhanced ferroptosis effect and immunogenic cell death (ICD). In addition, ADA degrades high-level adenosine to reverse the immunosuppressive microenvironment, thus amplifying antitumor immune responses. Via NIR-II photoactivatable ferroptosis-immunotherapy, SPH GA shows an improved effect to absolutely remove bilateral tumors and effectively suppress tumor metastases in subcutaneous 4T1 breast cancer models. This study presents a dual-enzyme-based nanoagent with controllable therapeutic actions for effective and precise cancer therapy.