Advances in lipid nanoparticles delivering genetic medicines for solid cancers

Nucleic acid lipid nanoparticle (LNP) technology has enabled the delivery of genetic medicines to solid tumors, opening new avenues for oncology therapeutics. Solid tumors present unique challenges to nucleic acid delivery because of their complex tumor microenvironment (TME), which acts as a barrier to NP delivery. Nevertheless, nucleic acid LNPs carry diverse genetic medicine modalities that can exert anti-cancer effects. The versatility of LNPs allows both local and systemic administrations for the delivery of gene therapy payloads to solid cancer, with the additional capability to selectively target specific cell types through conjugation of targeting ligands onto the LNPs. Genetic medicines delivered by LNPs can directly affect cancer cells, such as by suppressing oncogenic drivers and cancer pathways with small non-coding RNAs, or through overexpression of toxin genes or tumor suppressors. Non-cancer components of the tumor, such as tumor-associated vasculature, can also be targeted and disrupted to inhibit the structures that support tumor growth. Alternatively, LNP delivery of genetic medicines can indirectly elicit anti-tumor effects by modifying the immune state of the tumor environment through delivery of immunomodulatory cytokines, overexpression of activatable receptors to stimulate immune cells with agonists, or antigen-binding scaffolds to direct immunity towards a cancer cell. In this review, we summarize recent advances, challenges, and prospects of LNP delivery of genetic medicines to treat solid tumors.