Atheroma Niche‐Responsive Nanocarriers for Immunotherapeutic Delivery

The buildup of atherosclerotic plaque in blood vessels is a major cause of cardiovascular disease. This study describes the design of injectable, self‐assembled peptide amphiphile nanofibers (PAs) that have the potential to target atheroma and deliver therapeutics that reduce plaque burden. The PAs contain linkages that cleave in response to endogenous cues within the atherosclerotic niche, enabling controlled drug release.

Abstract

Nanomedicine is a promising, noninvasive approach to reduce atherosclerotic plaque burden. However, drug delivery is limited without the ability of nanocarriers to sense and respond to the diseased microenvironment. In this study, nanomaterials are developed from peptide amphiphiles (PAs) that respond to the increased levels of matrix metalloproteinases 2 and 9 (MMP2/9) or reactive oxygen species (ROS) found within the atherosclerotic niche. A pro‐resolving therapeutic, Ac2‐26, derived from annexin‐A1 protein, is tethered to PAs using peptide linkages that cleave in response to MMP2/9 or ROS. By adjusting the molar ratios and processing conditions, the Ac2‐26 PA can be co‐assembled with a PA containing an apolipoprotein A1‐mimetic peptide to create a targeted, therapeutic nanofiber (ApoA1‐Ac226 PA). The ApoA1‐Ac2‐26 PAs demonstrate release of Ac2‐26 within 24 h after treatment with MMP2 or ROS. The niche‐responsive ApoA1‐Ac2‐26 PAs are cytocompatible and reduce macrophage activation from interferon gamma and lipopolysaccharide treatment, evidenced by decreased nitric oxide production. Interestingly, the linkage chemistry of ApoA1‐Ac2‐26 PAs significantly affects macrophage uptake and retention. Taken together, these findings demonstrate the potential of PAs to serve as an atheroma niche‐responsive nanocarrier system to modulate the inflammatory microenvironment, with implications for atherosclerosis treatment.

http://bit.ly/2H0Dhm3