Antibody-functionalized lipid nanocarriers for RNA-based cancer gene therapy: advances and challenges in targeted delivery

Despite remarkable advances in cancer therapeutics, conventional treatments still face significant hurdles, including systemic toxicity, poor tumor specificity, multidrug resistance, and suboptimal intracellular delivery. Lipid-based nanocarriers (LBNCs) have emerged as versatile platforms for delivering therapeutic RNA molecules, offering biocompatibility and tunable properties that enhance drug stability and bioavailability. Functionalizing these nanocarriers with antibodies has unlocked new potential for achieving precise tumor targeting, leveraging the overexpression of specific receptors on cancer cells. This review provides a comprehensive and focused update on recent developments in antibody-decorated LBNCs designed for RNA-based cancer gene therapy. We discuss cutting-edge advances in conjugation chemistries, including site-specific strategies such as strain-promoted click reactions and Fc-glycan engineering, as well as the integration of emerging antibody formats, including nanobodies and single-domain antibodies. Furthermore, we present studies reporting the various LBNC formulations, including liposomes, solid lipid nanoparticles, lipid nanoparticles, and hybrid systems, highlighting their physicochemical characteristics, in vitro and in vivo performance, and the critical trade-offs between targeting specificity and endosomal escape efficiency. Epidemiological data underscore the pressing need for such innovations, particularly in aggressive and hard-to-treat cancers. While promising, clinical translation remains hindered by challenges in scalable manufacturing, regulatory approval, and biological complexity. Continued interdisciplinary research is essential to transform antibody-functionalized LBNCs from experimental strategies into clinically viable solutions for next-generation, RNA-based cancer therapies.