Mitochondria-targeted NIR-II organic probes for imaging-guided photodynamic therapy

Fluorescence imaging-guided photodynamic therapy (PDT) is a promising modality for precision cancer treatment, yet most organic photosensitizers emitting in the visible or first near-infrared (NIR-I) region suffer from limited penetration, strong photon scattering, and high tissue autofluorescence. Organic fluorophores with second near-infrared emission (NIR-II, >1000 nm) mitigate these constraints, enabling deeper imaging, improved spatial resolution, and higher signal-to-background ratios for accurate tumor delineation, real-time therapeutic guidance and longitudinal monitoring of PDT responses. Subcellular targeting further affects PDT efficacy and mechanism. Mitochondria are particularly attractive targets because they govern redox homeostasis and bioenergetics and function as central hubs for programmed cell death (PCD). Mitochondria-localized photosensitizers (PSs) generate reactive oxygen species (ROS) adjacent to cardiolipin-rich membranes and respiratory chain complexes, amplifying phototoxicity while reducing off-target oxidation. Consequently, mitochondria-targeted NIR-II fluorophores provide an integrated phototheranostic framework that couples high-contrast deep-tissue imaging with spatially confined PDT to modulate apoptosis, pyroptosis, ferroptosis, autophagy/mitophagy-associated death, and necroptosis. In this review, we summarize recent advances in mitochondria-targeted organic NIR-II fluorophores for PDT, highlighting photophysical principles and molecular design strategies. We also emphasize how mitochondria-localized NIR-II PDT enables programmable regulation of cell death pathways and enhances antitumor immune responses, thereby offering new opportunities to overcome therapeutic resistance and advance precision photomedicine.