Biomimetic nanoparticles loaded lutein functionalized by macrophage membrane for targeted amelioration pressure overload-induced cardiac fibrosis

Abstract

Lutein is a strong antioxidant with anti-inflammatory, anti-oxidative and cardioprotective effects and could be a promising candidate for the treatment of hypertensive heart disease (HHD), but is not clinically appealing because of its low oral bioavailability and main distribution in the eyes. To address this, a biomimetic drug delivery system-MMLNPs was established by coating macrophage membranes (MMs) onto lutein-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (LNPs). This study characterized the physical properties of biomimetic nanoparticles and examined the targeting capability, therapeutic effects and mechanism, and biosecurity of administering them for cardiac fibrosis therapy in the transverse aortic constriction (TAC) model and in vitro. Transmission electron microscope mapping and dynamic light scattering analysis proved that MMLNPs were spherical nanoparticles camouflaged by a layer of cell membrane and had negative zeta potential. Confocal laser scanning microscopy and flow cytometry analysis showed that MMs on the biomimetic nanoparticles hindered the phagocytosis of macrophages and facilitated the targeting of activated endothelial cells. Ex vivo fluorescence imaging experiments demonstrated the targeting of biomimetic nanoparticles to the injured heart. EdU assay indicated that MMLNPs have the same potential to inhibit angiotensin (Ang) II-induced cardiac fibroblast proliferation as free lutein. Furthermore, echocardiography showed that MMLNPs improved cardiac function and structure, and Masson staining and western blotting showed that MMLNPs ameliorated cardiac fibrosis. We found MMLNPs inhibited the interleukin (IL)-11/ERK signaling pathway which was up-regulated in the TAC model compared to the sham-operated mouse. Biochemical testing and hematoxylin and eosin staining proved that the long-term use of MMLNPs lacked biological toxicity. Collectively, MMLNPs might be a promising nanodrug delivery approach to attenuate pressure overload (PO)-induced cardiac fibrosis.