Zwitterionic Supramolecular Nanoassemblies With siRNA and Simvastatin as “Nanoscavenger” for Synergistic Atherosclerosis Treatment

Atherosclerotic vulnerable plaques contain various undesirable components, including excess cholesterol, efferocytosis-deficient macrophages, and inflammatory factors. However, conventional lipid-lowering drugs often show limited efficacy due to their inability to target the complex pathophysiology. Herein, innovative zwitterionic supramolecular nanoassemblies, termed PCDSC-S2P, are developed as the nanoscavenger to reduce and stabilize plaques. The nanoassemblies are based on zwitterionic poly(carboxybetaine)-modified β-cyclodextrin (β-CD) acting as a host molecule that encapsulates simvastatin (Sim) as a guest and absorbs small interfering RNA targeting calcium/calmodulin-dependent protein kinase II gamma (siCaMKIIγ) electrostatically. The PCDSC-S2P nanoassemblies are driven by host-guest interactions, electrostatic interactions, and hydrogen bonds. Moreover, the macrophage-targeting peptide modification directs nanoassemblies accumulation toward atherosclerotic plaques. Therefore, PCDSC-S2P, as the nanoscavenger, can act at the lesional plaque via β-CD-mediated cholesterol removal, Sim-driven lipid lowering, and siCaMKIIγ-enhanced efferocytosis synergistically. Consequently, the PCDSC-S2P treatment regulates the release of inflammatory cytokines and exhibits anti-inflammatory activity. Furthermore, PCDSC-S2P can significantly reduce plaque area and stabilize plaques in apolipoprotein E-deficient mice fed with a high-fat diet. Together, PCDSC-S2P shows great potential as a new delivery system in the development of small interfering RNA formulation, showing its promise for atherosclerosis treatment.