Photodynamic therapy (PDT) has emerged as an attractive alternative in cancer therapy, but its therapeutic effects are limited by the nonselective subcellular localization and poor intratumoral retention of small-molecule photosensitizes. Here a fiber-forming nanophotosensitizer (PQC NF) that is composed of mitochondria targeting small molecules of amphiphilicity is reported. Harnessing the specific mitochondria targeting, the light-activated PQC NFs produce approximately 110-fold higher amount of reactive oxygen species (ROS) in cells than free photosensitizers and can dramatically induce mitochondrial disruption to trigger intense apoptosis, showing 20-50 times better in vitro anticancer potency than traditional photosensitizers. As fiber-shaped nanomaterials, PQC NFs also demonstrated a long-term retention in tumor sites, solving the challenge of rapid clearance of small-molecule photosensitizers from tumors. With these advantages, PQC NFs achieve a 100% complete cure rate in both subcutaneous and orthotopic oral cancer models with the administration of only a single dose. This type of single small molecule-assembled mitochondria targeting nanofibers offer an advantageous strategy to improve the in vivo therapeutic effects of conventional PDT.

Smart conversion of supramolecular structures in vivo is an attractive strategy in cancer nanomedicine, which is usually achieved via specific peptide sequences. Here we developed a lysosomal targeting small-molecule conjugate, PBC, which self-assembles into nanoparticles at physiological pH and smartly converts to nanofibrils in lysosomes of tumor cells. Such a transformation mechanically leads to lysosomal dysfunction, autophagy inhibition, and unusual cytoplasmic vacuolation, thus granting PBC a unique anticancer activity as a monotherapy. Importantly, the photo-activated PBC elicits significant phototoxicity to lysosomes and shows enormous advantages in overcoming autophagy-caused treatment resistance frequently occurring in conventional phototherapy. This improved phototherapy achieves a complete cure of oral cancer xenografts upon limited administration. Our work provides a new paradigm for the construction of nonpeptide nanotransformers with biomedical activities.