Atherosclerosis (AS) is a complex cardiovascular disease driven by the interplay of dysregulated lipid metabolism, chronic inflammation, and immune dysfunction. Increasing evidence has revealed that the gut microbiota not only regulates host metabolic homeostasis but also actively contributes to the initiation and progression of AS through intricate interactions with the innate immune system. Microbial-derived signaling molecules, including lipopolysaccharides, outer membrane vesicles, extracellular nucleic acids, and TMAO, can activate Toll-like receptors, the NLRP3 inflammasome, and nucleic acid–sensing pathways, thereby promoting inflammatory cytokine production, endothelial dysfunction, and foam cell formation. In contrast, beneficial microbial metabolites such as short-chain fatty acids, bile acids, and tryptophan-derived metabolites exert immunomodulatory and vasculoprotective effects through signaling pathways involving FFAR2/3, the AhR, the FXR, and TGR5. Conversely, the innate immune system shapes microbial composition and function through barrier defense, phagocytic clearance, and antimicrobial factor production, establishing a dynamic and reciprocal microbiota–immune interaction network. This review systematically summarizes alterations in microbial ecology and innate immune homeostasis associated with atherosclerosis, elucidates the key molecular mechanisms underlying microbiota–innate immune crosstalk, and examines its dynamic involvement across four critical stages of disease evolution: endothelial dysfunction, foam cell formation, plaque progression, and plaque destabilization and rupture. In addition, emerging therapeutic approaches, including microbiota remodeling, modulation of microbial metabolic pathways, and precision microbiome-based interventions, are comprehensively discussed. The microbiota–innate immune axis provides a novel conceptual framework for understanding atherosclerosis pathogenesis and represents a promising target for future disease prevention, risk stratification, and precision therapeutics.
Yongang Li, Jinheng Zhu, Mingkui Huang et al.· Frontiers in Immunology· 0 citations
Frequent intravitreal administration of antivascular endothelial growth factor Vascular endothelial growth factor agents remains a major limitation in the management of wet age-related macular degeneration (wAMD). This study evaluated whether suprachoroidal delivery of an engineered recombinant adeno-associated viral (rAAV)-aflibercept vector could achieve sustained, targeted expression with improved efficacy and safety compared with intravitreal administration.
AL-001, an engineered rAAV vector expressing aflibercept, was developed and characterized. Its expression profile was first assessed in New Zealand white rabbits following suprachoroidal space (SCS) injection. Efficacy, pharmacokinetics, and safety were then evaluated in a nonhuman primate model of laser-induced choroidal neovascularization (CNV), comparing SCS and intravitreal (IVT) administration routes.
AL-001 efficiently expressed aflibercept in relevant ocular cells
in vitro
. In rabbits, SCS administration produced sustained aflibercept levels in ocular tissues. In the nonhuman primate CNV model, a single SCS injection of AL-001 showed favorable efficacy to IVT injection and a notable mild inflammatory response. At week 4, grade IV lesion incidence was 0% (0/48) after SCS administration versus 14.3% (6/42) after IVT administration (absolute difference, −14.3 percentage points; 95% CI, 3.7%–27.8%;
P
= 0.0258). Throughout follow-up, mean leakage area and grade IV lesion incidence remained 0 with SCS, versus IVT peaks of approximately 0.3 mm
2
and 33.0%, respectively, declining to 0.03 mm
2
and 2.0% by day 100. Both the medium and high doses decreased pathological vascular leakage and subretinal hyperreflective material. Vector administration preceded laser-induced CNV modeling, demonstrating that sustained intraocular aflibercept expression in the retina and choroid provided durable antiangiogenic protection. Pharmacokinetic analysis confirmed distinct ocular exposure profiles between routes, with viral genomes confined predominantly to the injected eye and no significant systemic accumulation. AL-001 was well tolerated, without sustained intraocular pressure elevation or severe ocular inflammation, and only mild-to-moderate treatment-emergent adverse events. Low pre-existing anti-AAV2 immunity and time-dependent neutralizing antibody responses postdosing, informing a translational model for patient stratification and redosing feasibility.
Suprachoroidal administration of AL-001 is well tolerated and provides durable, targeted aflibercept expression with pronounced antiangiogenic efficacy. These results support AL-001 as a promising, long-acting therapeutic candidate for wAMD.
Xuan Liu, Hai-Yan Liu, Lei Wang et al.· Frontiers in Genetics· 0 citations
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