Nanocarrier-Mediated Nucleic Acid Therapy in Non-Small Cell Lung Cancer: Converging Delivery Barriers, Resistance Reversal, and Clinical Translation
Lung cancer remains a leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) is the major histological subtype. Although chemotherapy, molecular targeted therapy, and immune checkpoint blockade have improved outcomes in selected patients, therapeutic resistance, tumor heterogeneity, systemic toxicity, and limited responsiveness still restrict durable clinical benefit. This review critically evaluates nanocarrier-mediated gene delivery for gene regulation, combination therapy, and resistance reversal in NSCLC. As a narrative review, this article integrates studies on nucleic acid nanomedicine relevant to NSCLC using a barrier-payload-resistance-translation framework, focusing on payload compatibility, intracellular trafficking, endosomal escape, immune safety, pharmacokinetics, biodistribution, and translational feasibility. Small interfering RNA (siRNA), microRNA (miRNA), antisense oligonucleotides (ASOs), and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) systems can modulate oncogenic signaling, resistance-associated pathways, and the tumor immune microenvironment. However, effective delivery requires overcoming nuclease degradation, mononuclear phagocyte clearance, heterogeneous tumor accumulation, stromal barriers, inefficient cellular uptake, insufficient endosomal escape, immune activation, and uncertain pharmacokinetic and biodistribution profiles. This review discusses lipid-based, polymeric, inorganic, bio-derived, and viral systems according to payload compatibility, intracellular delivery requirements, safety, and clinical feasibility. Particular emphasis is placed on resistance mechanisms beyond classical multidrug efflux, including epithelial-mesenchymal transition (EMT), cancer stem cell-associated resistance, DNA damage repair, bypass activation of targeted therapy pathways, immune escape, and metabolic reprogramming. Future nanocarrier-based gene therapy for NSCLC should move beyond material innovation toward barrier-informed, resistance-matched, biomarker-guided, and clinically scalable precision nanomedicine.