Abstract
Nanoparticle-based therapeutics hold promise for the treatment of atherosclerosis, but challenges such as low drug-loading capacity and a lack of scalable, controllable production hinder their clinical translation. Flash nanoprecipitation, a continuous synthesis method, offers a potential solution for scalable and reproducible nanoparticle production. In this study, we employed a custom-designed multi-inlet vortex mixer to perform cross-linking reaction-enabled flash nanoprecipitation, facilitating controlled and scalable synthesis of cross-linked polyamidoamine (PAMAM) dendrimer nanoparticles. Notably, this approach allows simultaneous nanoparticle cross-linking and drug loading in a single step. The mannose moiety enabled specific targeting of macrophages via mannose receptors, enhancing the localization of the nanoparticles to atherosclerotic plaques. Atorvastatin calcium, a widely used clinical drug for atherosclerosis treatment, was selected as the model drug. This approach achieved both high production rates and high drug-loading capacities, with an output flow rate of 9.6 L/h and a nanoparticle concentration of approximately 0.4 g/L. The optimized formulation exhibited a drug-loading capacity of 37% and an encapsulation efficiency of 76%. In vitro and in vivo experiments demonstrated effective macrophage and plaque targeting, leading to significant therapeutic benefits. Treatment with these nanoparticles resulted in approximately 40% inhibition of aortic root plaque progression compared to the free drug-treated group. This scalable and efficient nanoparticle platform is a promising strategy for improving atherosclerosis treatment.