Unlocking intracellular targets: Smart multistage-responsive polyionic vesicular platforms for advancing...

The intrinsic structural and physicochemical attributes of proteins are intrinsically associated with the limited ability of protein drugs to traverse cellular membrane barriers, thereby constraining their utility in regulating intracellular processes. To address this challenge, we developed a smart, multistage-responsive polyion complex vesicles (PICsomes) platform, engineered from biodegradable poly(amino acid) networks to overcome the sequential biological barriers encountered during protein delivery. PICsomes can encapsulate a range of proteins with different molecular weights and charge characteristics, and have demonstrated efficacy in the treatment of intractable diseases such as tumors and atherosclerosis. Functionalization with RGD-targeting ligands, which display high affinity for integrins overexpressed in tumor and atherosclerotic microenvironments, enables PICsomes to actively accumulate at lesion sites and enhance cellular internalization via endocytosis. Once internalized, the PICsomes exhibit precisely tuned spatiotemporal responsiveness to the acidic pH and reductive potential of the target microenvironment, triggering programmed protein release within subcellular compartments to achieve therapeutic effects. This platform thus represents a promising innovation and a potentially generalizable strategy for intracellular protein delivery, enabling more effective engagement with intracellular targets and expanding the scope of protein-based therapeutics.