Photo-responsive polyprodrug supramolecular assemblies with self-accelerated subcellular delivery for synergistic photochemotherapy

Targeted drug delivery with spatiotemporal control is critical for potent cancer therapy, yet inadequate subcellular delivery remains a major obstacle for DNA-targeted therapeutics due to multiple intracellular barriers. Herein, we report a photo-responsive polyprodrug supramolecular assembly to yield self-accelerated subcellular delivery of therapeutic cargoes for synergistic photochemotherapy against triple-negative breast cancer. The designed polyprodrug bears cleavable camptothecin pendants via thioketal-carbonate linkers and co-assembles with amphiphilic photosensitizers into ultrasmall supramolecular assembly, thereby affording sustained cargo release and enhanced singlet oxygen generation due to J-aggregate engineering of the photosensitizer within the assembly. Upon near-infrared light irradiation, the assembly elicits light-programmable drug release and lysosomal membrane disruption to facilitate rapid drug cytosolic translocation, followed by increased nuclear envelope permeability through lamin B1 downregulation and lipid peroxidation, thereby accelerating the permeation of cytosolic cargoes into the nucleus. Consequently, the self-accelerated intranuclear accumulation results in the eradication of intractable tumor through synergistic photochemotherapy. This study demonstrates a chemically programmed strategy for spatiotemporally-controlled subcellular delivery, providing a feasible avenue for highly effective cancer therapy.