Ionizable lipid nanoparticles with functionalized PEG-lipids increase retention in the tumor microenvironment

This study explores the efficacy of ionizable lipid nanoparticles (LNPs) modified with various functionalized polyethylene glycol (PEG)-lipids for retention within the tumor microenvironment after intratumoral (IT) injection. LNPs were synthesized and characterized with four different functionalized PEG-lipids, and the top performing lipids were evaluated under formulation conditions that varied the ratio of non-modified to functionalized PEG within the LNP. These LNPs were evaluated for size, polydispersity index, zeta potential, pKa, and mRNA encapsulation efficiency, with subsequent <i>in vitro</i> analysis of transfection and association efficiency to HepG2 liver cancer cells. Results demonstrated that LNPs formulated with PEG-folate and PEG-maleimide showed increased association to and interaction with cancer cells, compared with the base LNP formulation, which contained only non-functionalized lipid-PEG. <i>In vivo</i> studies showed increased retention of surface functionalized LNPs after IT injection in a xenograft model of hepatoblastoma. By slightly modifying LNPs in this manner, it is possible to develop delivery platforms that are better suited for local intratumoral administration. Ultimately, this research underscores the potential of LNPs as a vehicle for localized cancer therapy and emphasizes the need for future investigation into the long-term retention and therapeutic efficacy of LNP formulations.