Organelle-Function-Modulated In Situ Assembling Peptide Systems for Intracellular Drug Delivery

Abstract

In situ peptide assembly has emerged as a promising strategy for constructing bioactive materials that can dynamically respond to complex intracellular environments, offering improved spatiotemporal control, functional precision, and biocompatibility compared with conventional drug delivery systems. By integrating organelle-specific targeting with stimuli-responsive assembly, these systems enable localized therapeutic activation and precise modulation of intracellular organelle functions. This review summarizes recent advances in organelle-function-modulated in situ assembling peptide systems for intracellular drug delivery, with a particular focus on peptide assemblies targeting lysosomes, endoplasmic reticulum, Golgi apparatus, nucleus, and mitochondria. The fundamental design principles underlying these systems, including organelle targeting, microenvironment-responsive activation, programmable peptide assembly, functional regulation, and metabolic safety, are first discussed. Representative examples are then highlighted according to their therapeutic mechanisms, illustrating two distinct strategies: peptide assembly functioning directly as the therapeutic modality and peptide assembly serving as a carrier for therapeutic payloads. Emerging multi-organelle targeting approaches are also discussed to demonstrate how coordinated regulation of intracellular organelles may improve therapeutic efficacy. Finally, this review critically summarizes the current challenges associated with mechanistic understanding, in situ assembly characterization, biological safety, and clinical translation, and outlines future opportunities for the rational design of next-generation organelle-targeted peptide biomaterials. Overall, organelle-function-modulated in situ assembling peptide systems represent a versatile platform for precision intracellular therapeutics, although further advances in mechanistic studies, translational design, and in vivo validation will be essential for their future biomedical applications.