A pH and Light Dual-Responsive Spiropyran-Peptide Self-Assembly for Controlled Mitochondria and Nucleus Targeting

Subcellular targeting represents a highly attractive approach to the development of innovative nanomedicines. Herein, we present a peptide-spiropyran conjugate system that is responsive to both pH and light stimuli. Peptides 1-4 self-assemble in solution and undergo a morphological transition from nanofibers to nanoparticles upon pH or light stimulation. The assembly state exerts a profound influence on their targeting properties: while the nanofiber assemblies predominantly localize to mitochondria, the nanoparticle assemblies enable translocation to the cell nucleus. Furthermore, the gemcitabine conjugate (1-Gem) exhibits potent cytotoxicity against tumor cells, surpassing the efficacy of free gemcitabine by more than 10-fold. 1-Gem is capable of forming coacervates in solution, which can encapsulate additional chemotherapeutic agents. Notably, the combination of 1-Gem and doxorubicin achieves remarkable antitumor activity in the picomolar range. Thus, this work establishes a novel platform for enabling controlled organelle targeting with broad implications for the development of subcellular-targeted therapeutic strategies.