Targeted Collagen Degradation by an MRI Probe Facilitates siRNA Delivery for Sequential Theranostics in Pulmonary Fibrosis

Pulmonary fibrosis (PF) is characterized by dense collagen and mucus barriers that significantly limit drug delivery to the lungs. Clearing the collagen barrier can enhance drug delivery efficiency. Nevertheless, the heterogeneity of collagen states among patients poses a challenge. Therefore, real-time monitoring of the collagen clearance status is essential for PF personalized therapy. Herein, sequential theranostic platforms are proposed for collagen targeting and magnetic resonance imaging (MRI) monitoring to guide small interfering RNA (siRNA) delivery. First, for collagen barrier targeting-degrading, collagenase is conjugated with a collagen-targeting peptide capable of chelating the MRI contrast agent Gd(III), forming Col I T-D. This allows real-time, noninvasive MRI monitoring of the dynamic collagen clearance process. Second, guided by MRI, the zwitterionic polymer-based siRNA vectors (siTGF-β1@TZ) with mucus-penetrating and fibroblast-targeting capabilities are inhaled under an optimal state of collagen barrier. The sequential application of Col I T-D and siTGF-β1@TZ demonstrates significant lesion enrichment and therapeutic efficacy in PF treatment. Collectively, this study provides a novel perspective on dynamically monitoring collagen clearance status and guiding the sequential delivery of siRNA, offering a promising strategy for personalized PF therapy.