Topologically Engineered Supramolecular Cyclolipid Nanoparticles: A Custom-Tailored Delivery System for Inhaled Combination Therapy

Lipid nanoparticles (LNPs) have shown promising potential in the development of nucleic acid therapeutics and vaccines; however, unsatisfactory endosomal escape efficiency and physiological stability hinder their clinical applications. Herein, we design and synthesize a novel topologically engineered cyclodextrin-cored lipid (cyclolipid) featuring seven tertiary amine groups, seven secondary amine groups, and 14 hydrophobic alkyl tails to fabricate two-component supramolecular cyclolipid nanoparticles (CNPs). Benefiting from its cone-shaped structure, the cyclolipid facilitates the transition of endosomal membranes from the lamellar phase to the unstable hexagonal II phase, thereby promoting membrane destabilization and endosomal escape of CNPs. Additionally, the high density of ionizable sites enhances the binding capacity with RNA, while multiple hydrophobic alkyl chains strengthen the stability of CNPs, thus guaranteeing the in vivo circulation stability. Interestingly, the cavity of the cyclolipid enables the encapsulation of pirfenidone (PFD, an antifibrotic drug) through host–guest interactions, offering a promising strategy for synergistic therapy. Rationally optimizing the components and physicochemical properties of CNPs dramatically promotes mucus penetration capability, thereby enhancing their bioavailability in the lungs and avoiding unwanted side effects toward other organs. Leveraging their exceptional ability for achieving physiological stability, mucus penetration, and endosomal escape, siRNA targeting heat shock protein 47 (siHsp47) and PFD are codelivered by CNPs (CNPs@siHsp47/PFD) for the treatment of pulmonary fibrosis. CNPs@siHsp47/PFD synergistically alleviates pulmonary fibrosis, achieving therapeutic outcomes comparable to those of healthy mice, highlighting the outstanding potential of CNPs as the next-generation delivery platform for drug and gene combination therapy.