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 between genetic, molecular, and environmental factors. Standard treatments, including immunotherapy and targeted inhibitors, face three main challenges: tumor heterogeneity, drug resistance, and systemic toxicity. Nucleic acid therapeutics (NATs) include various DNA- and RNA-based tools which include small interfering RNA (siRNA) and microRNA (miRNA) and messenger RNA (mRNA) and antisense oligonucleotides (ASOs) and clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) systems to develop precision oncology which operates through direct gene regulation and mutation correction and immune system reprogramming. The clinical application of NATs currently faces obstacles because of three main issues, 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 together with exosomes and 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 will treat lung cancer. The current advancements indicate that we are approaching a transformative era in which nanomedicine and nucleic acid therapeutics will enable safe genetic alterations of cancer through targeted therapeutic applications. Conceptual illustration of a precision nanomedicine pipeline for personalized lung cancer therapy. The framework combines patient-derived multi-omics data with computational analysis to guide target and nucleic acid sequence selection, enabling the rational design of customized nano-vectors and personalized treatment strategies. AI: Artificial intelligence; ASO: Antisense oligonucleotide; CRISPR/Cas: Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein; EPR effect: Enhanced permeability and retention effect; miRNA: MicroRNA; NATs: Nucleic acid therapeutics; siRNA: Small interfering RNA. • Nucleic acid nanomedicines allow precise gene modulation and mutation correction in lung cancer. • Nano-delivery systems improve stability, uptake, and tumor-specific transport of DNA/RNA drugs. • Targeted, stimulus-responsive carriers enable site-specific and controlled payload release. • Artificial intelligence and multi-omics integration drive personalized and adaptive nanogenetic therapies. • These strategies help overcome resistance, heterogeneity, and toxicity of standard treatments.