Ant Colony-Inspired Adaptive Peptide Nanoregulators Remodeling the Endothelial Barrier to Alleviate Inflammatory Responses

Endothelial barrier disruption exacerbates inflammation and tissue injury, posing dual challenges of reconstructing tight junctions and precisely regulating the local microenvironment. Traditional multidrug therapies often struggle with rapid drug leakage due to barrier dysfunction and limited synergy between therapeutic agents. Here, a strategy is proposed inspired by the “ant colony collaboration”, developing an “all-in-one” conformationally adaptive peptide nanoregulator (VJP NPs) through the intelligent integration of three functional peptides. VJP NPs strategically harness the overexpression of vascular cell adhesion protein 1 (VCAM-1), enabling selective targeting of the inflamed endothelium under the guidance of the VHPK peptide while accumulating within the inflammatory microenvironment. The nanoregulators disassemble in response to high ROS levels, efficiently scavenging excess ROS. Simultaneously, they release the PMX peptide, competitively binding to the complement receptor C5aR to regulate the complement cascade. Furthermore, they release the JIP peptide to restore the endothelial barrier, reducing immune cell infiltration. As demonstrated in a mouse model of acute lung injury (ALI), VJP NPs markedly promote pulmonary vascular endothelial barrier repair, effectively attenuating inflammatory responses and alleviating tissue injury. This peptide-based nanoplatform boosts peptide delivery efficiency via a nanoprodrug strategy and amplifies synergistic therapeutic effects, highlighting its potential in endothelial barrier restoration and inflammation modulation.