Nanotheranostics alleviate vulnerable atherosclerotic plaques through lipid-specific photoacoustic imaging and hypoxic microenvironment modulation

Background Atherosclerosis, particularly vulnerable plaques, represents a significant risk factor for adverse cardiovascular events. Photoacoustic (PA) imaging, as a non-invasive modality, offers high resolution and tissue penetration, demonstrating substantial potential in the diagnosis of atherosclerotic cardiovascular diseases. Furthermore, the hypoxic microenvironment exacerbates plaque inflammation and instability, yet targeted therapeutic strategies remain lacking. Purpose This study aimed to develop a nanosystem combing lipid-specific PA imaging with hypoxic microenvironment modulation to achieve non-invasive, highly specific identification and early intervention of vulnerable atherosclerotic plaques. Methods Lipid-specific polymer PA probes were first designed and screened, then functionalized with metronidazole moieties. Subsequently, oxidized hyaluronic acid served as the hydrophilic scaffold, while selenocystamine-modified β-cyclodextrin functioned as the crosslinker to load HIF inhibitors and PA probes. The nanosystem was further surface-modified with CD14-targeting ligands, thereby yielding a targeted nanotheranostic platform (PCHL@IDF). The physicochemical characteristics were characterized. The cellular functional modulation to RAW 264.7 and MOVAS cells were studied in vitro. Furthermore, vulnerable atherosclerotic plaque models were established based on ApoE-/- Fbn1C1039G+/- mice and were administered different formulas to evaluate plaque-targeting specificity, lipid-specific PA imaging performance, and therapeutic efficacy. Results The particle size of PCHL@IDF was approximately 108.7 nm. Through in vitro PA imaging, it was observed that PCHL@IDF exhibited great PA properties with lipid- and concentration-dependent photoacoustic intensity at 710 nm. In vitro experiments demonstrated that PCHL@IDF could be efficiently internalized by foam cells, inhibit HIF-1α expression, reduce lipid accumulation, and modulate macrophage polarization and vascular smooth muscle cell phenotypic transformation. Flow cytometry found that the monocyte-hitchhiking strategy significantly enhanced the binding efficiency of the nanosystem to circulating monocytes in vivo and facilitated its efficient delivery to plaques. PA imaging revealed enhanced signals at plaques, with significantly stronger PA responses observed in lipid-rich plaques. In vivo therapeutic experiments in vulnerable atherosclerotic plaque models demonstrated that PCHL@IDF significantly reduced aortic plaque area and lipid accumulation, increased collagen composition, diminished the necrotic core, and ultimately enhanced plaque stability. Conclusions This nanosystem achieved lipid-specific identification of early vulnerable plaques through PA intensity, and effectively stabilized and reversed plaque progression by ameliorating local hypoxic microenvironment. This provides a promising nanotheranostic strategy for early-stage risk management of atherosclerosis.Figure 1Figure 2