Abstract / Summary
Abstract Background Posterior capsule opacification (PCO) remains the leading long-term complication after cataract surgery, driven by uncontrolled epithelial-mesenchymal transition (EMT) and fibrosis of residual lens epithelial cells. Currently, the only effective treatment is Nd: YAG laser capsulotomy, which is invasive and associated with potential complications. No pharmacological prophylaxis is available, highlighting an urgent need for a targeted, sustained-release platform to precisely interfere with PCO pathogenesis. Results Here, we engineer a novel IOL-based nanomedicine platform (LAPIs) that integrates a biodegradable PLGA sustained-release coating with lipid-nanoparticle (LNP)-encapsulated antisense oligonucleotide (ASO) targeting CTGF. The LNP-ASO complex exhibits uniform size (~ 79 nm), high encapsulation efficiency (> 92%), and efficient cellular uptake. The PLGA matrix enables controlled ASO release for over 28 days, with cumulative release reaching > 85% at 56 days. In vitro, ASO treatment (400 nM) significantly suppresses TGF-β2-induced cell proliferation, migration, and expression of fibrotic markers (α-SMA, Collagen I) at both mRNA and protein levels. Mechanistically, ASO simultaneously blocks canonical Smad2/3 and non-canonical PI3K-AKT/STAT3 pathways, as confirmed by western blotting and RNA-seq analysis. Importantly, using a rabbit PCO model that closely simulates the human intraocular environment after cataract surgery, LAPIs significantly attenuates PCO formation (mean PCO grade reduced from 3.4 to 1.2, p < 0.01) without detectable ocular or systemic toxicity within the 42-day observation period based on histological evaluation. Conclusions The efficacy of the ASO drug and the LAPIs sustained-release system is validated in two animal models: a mouse anterior capsule puncture model and a clinically relevant rabbit PCO model. This study provides the first preclinical proof-of-concept evidence for a nucleic-acid-based, nanoparticle-engineered sustained-release IOL system for PCO prevention in a rabbit model. Further validation in larger animal models and long-term safety studies are required before clinical translation can be considered. Graphical abstract Highlight A first-of-its-kind sustained-release IOL platform based on PLGA-engineered delivery of therapeutic antisense oligonucleotides.Controlled ASO release for >28 days via biodegradable PLGA reservoir, addressing key limitations of current drug-eluting IOLs.Multi pathway inhibition (Smad2/3, PI3K/AKT, STAT3) of lens EMT and fibrosis through targeted CTGF silencing.Promising in vivo efficacy and biosafety in a rabbit PCO model, suggesting potential for further translational development.