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 <b>1</b>-<b>4</b> 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 (<b>1-Gem</b>) exhibits potent cytotoxicity against tumor cells, surpassing the efficacy of free gemcitabine by more than 10-fold. <b>1-Gem</b> is capable of forming coacervates in solution, which can encapsulate additional chemotherapeutic agents. Notably, the combination of <b>1-Gem</b> 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.