Profiling miRNAs Involved in Human Oligodendrocyte Precursor Cell Differentiation and Maturation.

Atherosclerosis is a chronic inflammatory disease and remains the leading cause of cardiovascular mortality worldwide [, ]. Elevated levels of oxidized low‐density lipoprotein (oxLDL) in the circulation represent a critical link in the initiation and progression of atherosclerosis [, ]. The metabolic fate of oxLDL in vivo primarily involves two key aspects: generation and uptake []. On one hand, proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low‐density lipoprotein receptor (LDLR) on the surface of hepatocytes [, , , ], thereby reducing hepatic clearance of LDL and elevating circulating LDL‐C levels, which in turn increases the generation of oxLDL. On the other hand, in the local plaque vascular wall, oxLDL is primarily taken up via lectin‐like oxidized low‐density lipoprotein receptor‐1 (LOX‐1) expressed on the surface of endothelial cells and other cells. Binding of oxLDL to LOX‐1 activates downstream signaling pathways [, , ], leading to the release of pro‐inflammatory cytokines, enhanced oxidative stress, and endothelial dysfunction, thereby accelerating plaque formation and progression [, , ]. In recent years, therapeutic strategies targeting oxLDL generation have mainly focused on the PCSK9 pathway. Approved PCSK9 inhibitors, including the monoclonal antibodies evolocumab and alirocumab, as well as the small interfering RNA (siRNA) agent inclisiran, can significantly reduce circulating LDL‐C levels, decrease oxLDL generation, and lower the incidence of cardiovascular events [, ]. However, their direct intervention on local oxLDL uptake in the vascular wall and oxidative stress within plaques remains relatively limited. In contrast, drug development targeting oxLDL uptake is still largely confined to preclinical stages. Limited studies have shown that LOX‐1 inhibition can reduce oxLDL uptake, attenuate inflammation and oxidative stress, thereby improve the prognosis of atherosclerosis [, ]. Nevertheless, when circulating LDL‐C levels remain elevated, the persistent generation of oxLDL continues to drive disease progression. Therefore, in the current landscape of atherosclerosis treatment, combination therapeutic strategies that synergistically inhibit both the generation and utilization of oxLDL hold significant clinical necessity and potential value. Accordingly, this study proposes a novel therapeutic strategy for atherosclerosis that simultaneously targets PCSK9/LDLR‐mediated oxLDL generation and LOX‐1‐mediated local oxLDL uptake, thereby synergistically blocking the pathological metabolism of oxLDL at both the systemic and plaque‐local levels (Scheme ). To this end, we developed a plaque‐hepatic dual‐targeting engineered nanoparticle, designated as siPCSK9@PEAL NPs‐aL. This nanoparticle is constructed with a polyethylene glycol‐poly(lactic‐co‐glycolic acid)‐poly‐L‐lysine (PEG‐PLGA‐PLL, PEAL) framework, surface‐functionalized with anti‐LOX‐1 monoclonal antibody (anti‐LOX‐1 mAb) and electrostatically loaded with siPCSK9. The biodegradable PLGA core enables controlled release of siRNA [], while the cationic PLL layer facilitates efficient siRNA condensation, protects it from degradation, and promotes endosomal escape [, ]. Through surface modification with anti‐LOX‐1 mAb, the nanoparticles actively target LOX‐1‐overexpressing endothelial cells within atherosclerotic plaques, thereby blocking local oxLDL uptake and mitigating oxidative stress. Concurrently, by optimizing particle size, the nanoparticles achieve passive accumulation in the liver while bypassing rapid clearance by the reticuloendothelial system (RES), enabling effective delivery of siPCSK9 to hepatocytes. This leads to PCSK9 gene silencing and subsequent upregulation of LDLR, which reduces circulating native LDL levels and decreases oxLDL generation (Scheme ).