Self-Assembling Peptide Nanotherapeutics: Precision Targeting for Acute Lung Injury and Multimodal Intervention in Chronic Pulmonary Fibrosis

Self-assembling peptides have emerged as promising nonviral vectors for small interfering RNA (siRNA) delivery. Herein, we report DP7-C, a cholesterol-conjugated peptide capable of forming stable nanocomplexes with siRNA through self-assembly, and systematically elucidate its efficacy in pulmonary delivery through two distinct administration routes. Comparative studies demonstrated that intravenous administration of DP7-C/siRNA complexes resulted in significantly greater pulmonary accumulation than nebulization. This enhanced accumulation was attributed to the ability of DP7-C to facilitate siRNA internalization specifically through peptide-LDL receptor interactions, thereby overcoming key physiological barriers. Further biodistribution analysis revealed that intravenously administered DP7-C/siRNA primarily accumulated in pulmonary epithelial and endothelial cells in mice with inflammation. Leveraging this targeted delivery capability, we first validated DP7-C-mediated IV delivery of single-target ICAM-1 siRNA for acute lung injury treatment, which markedly attenuated pulmonary inflammation by reducing neutrophil infiltration and proinflammatory cytokine levels. Furthermore, a combinatorial siRNA strategy targeting MMP7, CXCL12, and TGFβ delivered by DP7-C effectively mitigated bleomycin-induced pulmonary fibrosis in vivo, as evidenced by decreased inflammatory response and collagen deposition, and also downregulated fibrotic markers. Our findings highlight DP7-C as a versatile platform for lung-targeted siRNA delivery, offering dual therapeutic potential for both acute inflammatory and chronic fibrotic pulmonary disorders through route-optimized administration and multitarget gene silencing strategies.