Reengineering glycyrrhetinic acid into a therapeutic oligomer for targeted tumor therapy with cardioprotection

Abstract To overcome the inherent limitations of conventional nanocarriers such as therapeutic inefficacy and suboptimal drug loading capacity, a novel “polymeric nanodrug” strategy was developed. This approach redefines nanodrug design by employing glycyrrhetinic acid (GA) simultaneously as a bioactive agent and a polymerizable targeting monomer to synthesize poly-glycyrrhetinic acid (PGA), achieving near-theoretical drug loading approaching 100%. Subsequent PEGylation yielded hepatocellular carcinoma (HCC)-targeting PGA-PEG-GA nanodrugs, which exhibited a 1.89-fold enhancement in antitumor efficacy compared to free GA. The exceptionally low critical micelle concentration (CMC) of PGA-PEG-GA enables efficient encapsulation of additional therapeutics. Using doxorubicin (DOX) as a model drug, HCC-targeting nanodrugs (denoted as DOX@PGA-PEG-GA NDs) were fabricated. In vitro studies demonstrated that the nanodrugs induced 2.5-fold higher toxicity in tumor cells than normal cells, enhanced cellular uptake by 3.0-fold, and reduced DOX-induced cardiomyocyte apoptosis by 54%. In vivo evaluations revealed a tumor inhibition rate of 89.7 ± 5.2% for DOX@PGA-PEG-GA NDs and 40.09 ± 11.94% for blank PGA-PEG-GA NDs, together with 18.3-fold higher intra-tumoral accumulation compared to free DOX and complete mitigation of DOX-related cardiotoxicity. This integrated “structure-function-safety” strategy effectively overcomes critical challenges in drug-loading efficiency and functional synergy, offering a robust and novel platform for targeted nanodrug applications. Graphical Abstract