From Sequence to Site: RNA Therapeutics and Direct Pulmonary Delivery in Lung Cancer

More than three decades have passed since gene therapy potential was first recognized, following the first clinical trials, marking the beginning of a new era in targeted cancer therapy. Despite its early promise, the clinical development of gene therapy progressed slowly due to major safety concerns, limited efficiency of early vectors, and stringent regulatory constraints. Recent advances in vector engineering and genome editing technologies have revitalized the field, while innovative direct drug delivery approaches represent a promising approach to enhance gene delivery in oncology. Although encouraging results have been reported across various cancer types, the application of these delivery modalities in lung cancer remains limited due to a range of clinical and translational challenges. This review provides a comprehensive overview of recent both approved and investigational RNA-based candidates, with a focus on their application in lung cancer. As an emerging strategy, we discuss the potential of direct pulmonary drug delivery (DPDD) as a valuable approach to improve the precision, efficacy, and safety of gene therapy Additionally, we analyze in vivo studies used to evaluate DPDD strategies, underscoring their translational relevance and the challenges that must be addressed to enable clinical implementation. By synthesizing advances from 2020 to 2025, this review outlines the current landscape and future directions for RNA therapeutics and localized delivery systems in lung cancer.