Targeted PERK inhibition with biomimetic nanoclusters confers preventative and interventional benefits to elastase-induced abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) is a progressive aortic dilatation, causing ∼80% mortality upon rupture. Currently, there is no approved drug therapy for AAA. Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which, however, account for ∼90% of the newly diagnosed cases. It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression. We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods. There is substantial evidence that degenerative smooth muscle cells (SMCs) orchestrate AAA pathogenesis and progression. In this study, we made an exciting finding that PERK, the endoplasmic reticulum (ER) stress Protein Kinase R-like ER Kinase, is a potent driver of SMC degeneration and hence a potential therapeutic target. Indeed, local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo. In parallel, we also conceived a biomimetic nanocluster (NC) design uniquely tailored to AAA-targeting drug delivery. This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating; and when loaded with a selective PERK inhibitor (PERKi, GSK2656157), the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA. In summary, our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis, but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.

Dietary therapy in abdominal aortic aneurysm - Insights from clinical and experimental studies.

Abdominal aortic aneurysm (AAA) is a prevalent vascular disease with high mortality rates upon rupture. Despite its prevalence in elderly populations, there remain limited treatment options; invasive surgical repair, while risky, is the only therapeutic intervention with proven clinical benefits. Dietary factors have long been suggested to be closely associated with AAA risks, and dietary therapies recently emerged as promising avenues to achieve non-invasive management of a wide spectrum of diseases. However, the role of dietary therapies in AAA remains elusive. In this article, we will summarize the recent clinical and pre-clinical efforts in understanding the therapeutic and mechanistic implications of various dietary patterns and therapeutic approaches in AAA.

Biomimetic, ROS-detonable nanoclusters - A multimodal nanoplatform for anti-restenotic therapy.

The long-term success of endovascular intervention has long been overshadowed by vessel re-occlusion, also known as restenosis. Mainstream anti-restenotic devices, such as drug-eluting stent (DES) and drug-coated balloon (DCB), were recently shown with suboptimal performances and life-threatening complications, thereby underpinning the urgent need for alternative strategies with enhanced efficacy and safety profile. In our current study, we engineered a multimodal nanocluster formed by self-assembly of unimolecular nanoparticles and surface coated with platelet membrane, specifically tailored for precision drug delivery in endovascular applications. More specifically, it incorporates the combined merits of platelet membrane coating (lesion targetability and biocompatibility), reactive oxygen species (ROS)-detonable "cluster-bomb" chemistry (to trigger the large-to-small size transition at the target site, thereby achieving longer circulation time and higher tissue penetration), and sustained drug release. Using RVX-208 (an emerging anti-restenotic drug under clinical trials) as the model payload, we demonstrated the superior performances of our nanocluster over conventional poly(lactic-co-glycolic acid) (PLGA) nanoparticle. In cultured vascular smooth muscle cell (VSMC), the drug-loaded nanocluster induced effective inhibition of proliferation and protective gene expression (e.g., APOA-I) with a significantly reduced dosage of RVX-208 (1 µM). In a rat model of balloon angioplasty, intravenous injection of Cy5.5-tagged nanocluster led to greater lesion targetability, improved biodistribution, and deeper penetration into injured vessel walls featuring enriched ROS. Moreover, in contrast to either free drug solution or drug-loaded PLGA nanoparticle formulation, a single injection with the drug-loaded nanocluster (10 mg/kg of RVX-208) was sufficient to substantially mitigate restenosis. Additionally, this nanocluster also demonstrated biocompatibility according to in vitro cytotoxicity assay and in vivo histological and tissue qPCR analysis. Overall, our multimodal nanocluster offers improved targetability, tissue penetration, and ROS-responsive release over conventional nanoparticles, therefore making it a highly promising platform for development of next-generation endovascular therapies.