Use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in atherosclerosis.

ABSTRACT

Dysfunction in the macrophage lysosomal system including reduced acidity and diminished degradative capacity is a hallmark of atherosclerosis, leading to blunted clearance of excess cellular debris and lipids in plaques and contributing to lesion progression. Devising strategies to rescue this macrophage lysosomal dysfunction is a novel therapeutic measure. Nanoparticles have emerged as an effective platform to both target specific tissues and serve as drug delivery vehicles. In most cases, administered nanoparticles are taken up non-selectively by the mononuclear phagocyte system including monocytes/macrophages leading to the undesirable degradation of cargo in lysosomes. We took advantage of this default route to target macrophage lysosomes to rectify their acidity in disease states such as atherosclerosis. Herein, we develop and test two commonly used acidic nanoparticles, poly-lactide-co-glycolic acid (PLGA) and polylactic acid (PLA), both in vitro and in vivo. Our results in cultured macrophages indicate that the PLGA-based nanoparticles are the most effective at trafficking to and enhancing acidification of lysosomes. PLGA nanoparticles also provide functional benefits including enhanced lysosomal degradation, promotion of macroautophagy/autophagy and protein aggregate removal, and reduced apoptosis and inflammasome activation. We demonstrate the utility of this system in vivo, showing nanoparticle accumulation in, and lysosomal acidification of, macrophages in atherosclerotic plaques. Long-term administration of PLGA nanoparticles results in significant reductions in surrogates of plaque complexity with reduced apoptosis, necrotic core formation, and cytotoxic protein aggregates and increased fibrous cap formation. Taken together, our data support the use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in the treatment of atherosclerosis.Abbreviations BCA brachiocephalic arteries; FACS fluorescence activated cell sorting; FITC fluorescein-5-isothiocyanatel; IL1B interleukin 1 beta; LAMP lysosomal associated membrane protein; LIPA/LAL lipase A, lysosomal acid type; LSDs lysosomal storage disorders; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MFI mean fluorescence intensity; MPS mononuclear phagocyte system; PEGHDE polyethylene glycol hexadecyl ether; PLA polylactic acid; PLGA poly-lactide-co-glycolic acid; SQSTM1/p62 sequestosome 1.