Sterically Twisted Mitochondria‐Targeting Photosensitizers for Augmented Near‐Infrared II Fluorescence‐Guided Photodynamic Immunotherapy

Abstract Near‐infrared (NIR) fluorescent mitochondria‐targeting photosensitizers (PSs) hold great potential for efficient image‐guided cancer phototherapy, but it remains challenging to develop PSs concurrently integrating high‐contrast NIR‐II fluorescence imaging and efficient therapeutic capabilities. Herein, a heptamethine cyanine (HCy) PS (termed I 2 HCy‐TPE nanoparticles (NPs)) by a molecular engineering strategy combining the heavy atom effect and structural distortion is reported. The heavy atom iodine is introduced to boost the intersystem crossing process, and the bulky tetraphenylethylene (TPE) moiety placed at the meso‐position of the heptamethine chain creates a highly distorted conformation in I 2 HCy‐TPE, theoretically verified by density functional theory calculations. This strategy synergistically promotes the 1 O 2 generation efficiency and assure the strong NIR fluorescence emission in aggregated states. Combining with the intrinsic mitochondria‐targeting capability, I 2 HCy‐TPE NPs are able to cause mitochondria‐targeted damage of cancer cells via the PDT and immunogenetic cell death‐triggered immune responses under NIR laser irradiation. In vivo experiments demonstrate that the biocompatible I 2 HCy‐TPE NPs present exceptional capability for in vivo NIR‐II fluorescence bioimaging of whole‐body and blood vessels, and exert efficient NIR‐II fluorescence‐guided photodynamic immunotherapy against triple‐negative breast cancer.