<p>Cancer continues to be one of the top killers worldwide. Traditional treatment strategies like chemotherapy, radiation, and surgery have non-specific treatment options with considerable side effects. Gene-based therapies using nucleic acids like siRNA, miRNA, and DNAzymes provide an alternative approach; however, issues with stability, delivery, and off-target effects continue to plague their clinical use. Niosomes, or non-ionic surfactant vesicles, provide a flexible and inexpensive alternative to circumvent many of these issues. This review will present the niosomal systems for nucleic acid delivery in cancer therapy. Niosomes have key advantages compared to traditional delivery vehicles due to their chemical stability and biocompatibility, and ease of surface modifications. Their ability to carry a range of nucleic acids and allow for endosomal escape makes niosomes ideal candidates for targeted, multimodal therapies. Critical therapeutic applications include co-delivery of nucleic acids with chemotherapeutic drugs to improve synergistic activity, reprogramming the tumor microenvironment to increase immune response, and bypassing mechanisms of tumor resistance. In addition, the incorporation of external triggers, such as magnetic and ultrasound responsive elements, provides precise spatiotemporal control over nucleic acid release. The review outlines exciting research improvements of niosomal formulations based on surface charge, ligand targeting, and new genetic payloads, underscoring the state-of-the-art potential of niosomes for personalized cancer treatments. niosomes showed low immunogenicity and good pharmacokinetics in preclinical research, suggesting they are highly translational and leading-edge for next-generation cancer treatments.</p> Graphical abstract <p></p>