ROS-Scavenging Single-Component Polymeric Nanocarriers for Precision siRNA Delivery in Pulmonary Fibrosis Therapy.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive refractory lung disorder with limited effective therapies. Although RNA interference (RNAi) holds promise for IPF treatment, current delivery systems are hampered by complex preparation, redundant components, and an inability to modulate oxidative stress, which severely compromises their therapeutic outcomes. Herein, we design a single-component, lung-targeted nanosystem, PPN@siIL11, that simplifies formulation while integrating dual functions of efficient siRNA delivery and reactive oxygen species (ROS) scavenging. Upon intravenous administration, this streamlined platform exhibits enhanced pulmonary accumulation, effectively silences the profibrotic gene IL11, and suppresses fibroblast-to-myofibroblast transdifferentiation and excessive extracellular matrix deposition. Concurrently, it scavenges overproduced ROS to alleviate oxidative stress-mediated lung damage. Both in vitro and in vivo results demonstrate the potent anti-fibrotic efficacy of PPN@siIL11. By overcoming critical drawbacks of conventional multi-component carriers, this multifunctional single-component platform establishes a translatable approach for RNAi-based IPF therapy, with potential applicability to other lung diseases.