A multi-parameter-induced activation of gas therapeutic platform to remarkably amplify photodynamic therapy efficacy

Gas therapy (GT) combined with photodynamic therapy (PDT) is an effective strategy to compensate for the PDT limitation caused by the hypoxic tumor microenvironment, which can greatly improve PDT efficacy. The uncontrolled leakage of gas molecules during delivery seriously hinders its practical biological application. Herein, we report a multifunction nanomedicine that enables precise gas therapy (including carbon monoxide (CO) release and H₂S depletion) using a multi-parameter-induced activation gas release strategy, enlarging the PDT efficacy. This nanomedicine uses a disulfide bond to covalently link a photosensitizer with the CO donor 3-hydroxyflavone (3-HF). The disulfide bond can be specifically consumed in H₂S-rich tumor areas, releasing the CO donor (3-HF), and also depleting H₂S. More importantly, the photo-controlled production of ¹O₂ can induce 3-HF precise release of CO in the tumor location. Such H₂S, light, and ¹O₂ multi-parameter-induced activation of gas release strategy ensures the accuracy of GT to amplify PDT efficiency. As expected, in vitro and in vivo investigations show that GT makes up for the PDT limitation, exhibiting the highest tumor therapeutic effect. This multi-parameter-activated design strategy provides a new way to improve the precision and efficacy of multimodal synergistic therapy of tumorsy of tumors..