Inhalable Degradation‐Tunable Hybrid Nanoparticles With Rapid Lysosomal Escape for Dual siRNA Therapy Against NSCLC

The efficacy of gene therapy for lung cancer remains constrained by inadequate tumor targeting and insufficient penetration. Compounding this issue, conventional lipid-based gene vectors face the clinical challenges of instability induced by nebulization shear forces and severe toxicity caused by excessive positive surface charge. Herein, we engineered inhalable rigid polyester shell-lipid core hybrid nanoparticles (HNPs) capable of passive targeting upon pulmonary delivery, harnessing the complementary advantages of both liposomes and polymer nanoparticles. Systematic screening of shell type and molecular weight revealed a synergistic interplay between acid-labile rapidly degrading polyesters and lipids that simultaneously enhanced vibrating-mesh nebulization stability, pulmonary deposition, mucus and tumor penetration, while remarkably enabling rapid and sustained endo/lysosomal escape, thereby safely elevating short-term transfection efficiency in lung cancer cells and fibroblasts. To overcome the limited efficacy of single-target therapy, a dual siRNA delivery approach was employed, whereby the TGF-β pathway was first silenced to remodel the tumor microenvironment and the undruggable mutant KRAS oncogene was subsequently silenced, leading to tumor growth suppression and reduced metastasis. Collectively, a vector-drug dual-synergy strategy was established that systematically amplifies the therapeutic efficacy of gene therapy against NSCLC. Coupled with microfluidics-enabled scalable manufacturing and commercial nebulizer-compatible inhalability, HNPs hold promise for clinical translation.