A self-assembling nanoplatform for pyroptosis and ferroptosis enhanced cancer photoimmunotherapy

Abstract The microenvironment of immunosuppression and low immunogenicity of tumor cells has led to unsatisfactory therapeutic effects of the currently developed nanoplatforms. Immunogenic cell death, such as pyroptosis and ferroptosis, can efficiently boost antitumor immunity. However, the exploration of nanoplatform for dual function inducers and combined immune activators that simultaneously trigger pyroptosis and ferroptosis remains limited. Herein, a multifunctional pH-responsive theranostic nanoplatform (M@P) is designed and constructed by self-assembly of aggregation-induced emission photosensitizer MTCN-3 and immunoadjuvant Poly(I: C), which are further encapsulated in amphiphilic polymers. This nanoplatform is found to have the characteristics of cancer cell targeting, pH response, near-infrared fluorescence imaging, and lysosome targeting. Therefore, after targeting lysosomes, M@P can cause lysosome dysfunction through the generation of reactive oxygen species and heat under light irradiation, triggering pyroptosis and ferroptosis of tumor cells, achieving immunogenic cell death, and further enhancing immunotherapy through the combined effect with the immunoadjuvant Poly(I: C). The anti-tumor immunotherapy effect of M@P has been further demonstrated in in vivo antitumor experiment of 4T1 tumor-bearing mouse model with poor immunogenicity. This research would provide an impetus as well as a novel strategy for dual function inducers and combined immune activators enhanced photoimmunotherapy.