From Liposomes to Depot-Enabled Lipid-Gel Hybrid Nanocarriers: Evolving Strategies for Targeted and Sustained Anticancer Drug Delivery

Background: Conventional chemotherapeutics suffer from poor solubility, rapid clearance, nonspecific biodistribution, and narrow therapeutic indices that drive systemic toxicity. Liposomal and lipid-based nanocarriers offer a promising strategy to overcome these limitations by enhancing drug solubility, protecting labile agents, and modulating pharmacokinetics and biodistribution. Scope and Objectives: This review synthesizes current advances in liposomal nanomedicine, focusing on structural and physicochemical design principles, PK/PD advantages, and translational progress in oncology. We highlight clinical evidence supporting approved liposomal formulations, emerging applications beyond cytotoxic delivery, and persistent challenges that impede broader clinical integration. The goal is to provide a concise, mechanism-driven overview and outline key priorities for next-generation liposomal therapeutics. Key Insights: Liposomes, with their bilayer–aqueous core architecture, accommodate diverse therapeutic cargos while enhancing stability and bioavailability. Clinically validated formulations, such as liposomal anthracyclines and liposomal irinotecan, demonstrate reduced toxicity and improved tolerability versus free drugs. Advances in engineering including PEGylation, ligand-mediated targeting, stimuli-responsive release, and co-delivery are expanding their therapeutic landscape. However, inconsistent tumor penetration, variability of the EPR effect in human tumors, PEG-related immunogenicity, and challenges in large-scale manufacturing, storage stability, and reproducibility continue to restrict clinical translation. Conclusions & Outlook: Liposomal nanocarriers continue to serve as a versatile platform for cancer treatment and are also being explored for use in new approaches like immunotherapy and gene delivery. Future progress will depend on optimizing active targeting, exploring non-immunogenic surface chemistries, standardizing scalable production, and improving preclinical models. A rational, stepwise design strategy is essential to advance liposomal systems toward reliable, safe, and clinically impactful nanomedicine.