Advances in Drug Delivery Systems Utilizing Glycyrrhizic Acid and Its Aglycone Glycyrrhetinic Acid in Cancer Therapy

Glycyrrhizic acid (GL) and glycyrrhetinic acid (GA) exhibit antitumor activity, favorable biocompatibility, receptor-targeting capabilities, and amphiphilicity. These properties make them promising multifunctional components for developing antitumor drug delivery systems. Unlike previous reviews that focus on individual applications, this review systematically categorizes GL/GA according to their three functional roles. First, as therapeutic agents, GL/GA can be incorporated into passively targeted, actively targeted, and stimuli-responsive nanocarriers. They can be combined with chemotherapeutic drugs, such as cisplatin and paclitaxel, to enhance therapeutic efficacy and reduce systemic toxicity. Second, as targeting ligands, GL/GA can be conjugated to the surfaces of nanocarriers to enable receptor-mediated tumor delivery. Finally, as self-assembling materials, GL/GA can co-assemble with other drugs to form carrier-free nanostructures. Alternatively, they can serve as building blocks for polymeric carriers. These strategies enable drug-carrier integration, simplify formulation processes, and enhance synergistic antitumor effects. Furthermore, this review analyzes the key challenges in the clinical translation of these formulations. These challenges include the complexity of large-scale production, insufficient in vivo stability, a lack of long-term safety data, and inconsistencies in quality evaluation systems. Future translational prospects are also outlined to guide the rational design and clinical development of natural product-based nanomedicines.