Full-active pharmaceutical ingredient nanosensitizer for augmented photoimmunotherapy by synergistic mitochondria targeting and immunogenic death inducing

The precise and effective activation of the immune response is crucial in promising therapy curing Cancer. Photoimmunotherapy (PIT) is an emerging strategy for precise regulation and highly spatiotemporal selectivity. However, this approach faces a significant challenge due to the off-target effect and the immunosuppressive microenvironment. To address this challenge, a nanoscale full-active pharmaceutical ingredient (API) photo-immune stimulator was developed. This formulation overcomes the limitations of PIT by strengthening the ability to penetrate tumors deeply and inducing precise and potent mitochondria-targeted dual-mode photodynamic therapy and photothermal therapy. Along with inhibiting overexpressed HSP90, this nanosensitizer in turn improves the immunosuppressive microenvironment. Ultimately, this mitochondria-targeted PIT demonstrated potent antitumor efficacy, achieving a remarkable inhibition rate of ≥95% for both established primary tumors and distant abscopal tumors. In conclusion, this novel self-delivery full-API nanosystem enhances the efficacy of phototherapy and reprograms the immunosuppressive microenvironment, thereby holding great promise in the development of precise and effective immunotherapy.

full‐API nanosystem; heat shock protein; immunogenic cell death; mitochondria targeting; photoimmunotherapy.