A Dual‐Targeting, Multi‐Faceted Biocompatible Nanodrug Optimizes the Microenvironment to Ameliorate Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a highly lethal cardiovascular disease that currently lacks effective pharmacological treatment given the complex pathophysiology of the disease. Here, single‐cell RNA‐sequencing data from patients with AAA and a mouse model are analyzed, which reveals pivotal pathological changes, including the M1‐like polarization of macrophages and the loss of contractile function in smooth muscle cells (SMCs). Both cell types express the integrin αvβ3, allowing for their dual targeting with a single rationally designed molecule. To this end, a biocompatible nanodrug, which is termed EVMS@R‐HNC, that consists of the multifunctional drug everolimus (EVMS) encapsulated by the hepatitis B virus core protein modifies to contain the RGD sequence to specifically bind to integrin αvβ3 is designed. Both in vitro and in vivo results show that EVMS@R‐HNC can target macrophages as well as SMCs. Upon binding of the nanodrug, the EVMS is released intracellularly where it exhibits multiple functions, including inhibiting M1 macrophage polarization, thereby suppressing the self‐propagating inflammatory cascade and immune microenvironment imbalance, while preserving the normal contractile function of SMCs. Collectively, these results suggest that EVMS@R‐HNC presents a highly promising therapeutic approach for the management of AAA. By incorporating a hepatitis B virus core protein monomer with an RGD peptide modification and integrating the therapeutic drug EVMS through self‐assembly, the EVMS@R‐HNC construct specifically targets and facilitates the conversion of pro‐inflammatory M1‐like macrophages into anti‐inflammatory M2‐like macrophages, thereby suppressing the secretion of pro‐inflammatory cytokines and ameliorating the inflammatory microenvironment.