HMSN-Mediated miR-502-3p Delivery Suppresses Lung Adenocarcinoma via TPX2-Dependent Inhibition of PI3K/AKT

Lung adenocarcinoma (LUAD) is a prevalent subtype of nonsmall cell lung cancer with high mortality, underscoring the need for novel therapeutic strategies. Here, we demonstrated that the intravenous delivery of miR-502-3p via hollow mesoporous silica nanoparticles (HMSN; miR@HM-NH 2 ) dramatically suppresses LUAD xenograft growth with negligible toxicity. MiR-502-3p is significantly downregulated in LUAD tissues and correlates with poor differentiation, metastasis, advanced TNM stage, and reduced overall survival, as shown by clinical samples and TCGA analysis. In vitro, miR-502-3p overexpression inhibited proliferation, migration, and invasion in LUAD cell lines, including PC9 and H1975 cells. Mechanistically, dual-luciferase assays and RNA-seq identified TPX2 as a direct target of miR-502-3p. miR-502-3p-mediated TPX2 inhibition downregulated phosphorylation of PI3K and AKT, with no reciprocal regulation on TPX2. Collectively, our findings reveal that the miR-502-3p/TPX2/PI3K/AKT axis plays a critical tumor-suppressive role in LUAD, with HMSN-based miR-502-3p delivery offering a promising therapeutic strategy.