Beyond chemotherapy: The rise of nucleic acid nanoformulations in personalized lung cancer therapy

Lung cancer remains the leading cause of cancer-related mortality worldwide, driven by complex crosstalk among genetic, molecular, and environmental factors. Conventional treatments, including immunotherapies and targeted inhibitors, face three main challenges: tumor heterogeneity, drug resistance, and systemic toxicity. Nucleic acid therapeutics (NATs) encompass a diverse array of DNA- and RNA-based tools, including small interfering RNA (siRNA), microRNA (miRNA), messenger RNA (mRNA), antisense oligonucleotides (ASOs), and clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) systems. These tools are central to developing precision oncology approaches that operate through direct gene regulation, mutation correction, and immune system reprogramming. The clinical application of NATs currently are limited by three major challenges, which include their vulnerability to enzymatic degradation, their limited ability to penetrate tissues, and their tendency to cause off-target effects. The field has progressed through the implementation of nanoformulation techniques, which utilize lipid-based polymeric, and metallic carriers, along with exosomes, DNA origami, and hybrid nanostructures as new platforms to enhance the stability of drugs and their cellular absorption and targeted delivery to tumors. The scientists developed functionalized nanocarriers by combining targeting ligands with materials that could respond to specific environmental changes, which allowed them to manage drug distribution and release patterns throughout the tumor microenvironment. This review focuses on establishing a direct connection between nucleic acid design and nanotechnology through an analysis of mechanistic details and progress in preclinical and clinical research, and the difficulties encountered during the progress to practical applications. The research demonstrates how artificial intelligence and bioinspired nanocarriers and multi-omics data integration create new opportunities for developing personalized adaptive nanogenetic treatment methods, which may contribute to future lung cancer therapeutic strategie. Current technological trajectories indicate that the convergence of nanomedicine and nucleic acid therapeutics is ushering in a transformative era of precision oncology, enabling the highly selective modulation of tumor-specific genetic and transcriptomic pathways while mitigating off-target toxicities.