From bench to bedside: Advancing liposomal doxorubicin for targeted cancer therapy

Abstract

Liposomes have emerged as a transformative platform for targeted drug delivery in cancer therapy, addressing key limitations of traditional chemotherapeutics like doxorubicin (DOX. Although conventional anthracyclines are highly effective, their severe cardiotoxicity and systemic side effects restrict their clinical use. Liposomal encapsulation enhances this approach by encapsulating drugs within lipid bilayers, enabling controlled release, improved tumor targeting, and reduced off-target toxicity. Notably, PEGylated liposomal DOX formulations, such as Doxil®, have significantly improved pharmacokinetics, extended circulation times, and decreased cardiotoxicity while maintaining strong anticancer efficacy. This review systematically analyzes the development of liposome-based formulations for DOX, from early advancements to next-generation functionalized formulations. We critically examine recent innovations, including antibody-, peptide-, aptamer-, and cell-penetrating peptide-conjugated liposomes, which have demonstrated enhanced tumor specificity and the potential to overcome multidrug resistance. Additionally, thermosensitive liposomes (TSLs), particularly lyso-thermosensitive variants, present a promising strategy for localized drug release triggered by hyperthermia. Concurrently, pH-sensitive and sugar-conjugated liposomes exploit the unique characteristics of the tumor microenvironment for precise targeting. Despite these advancements, significant challenges remain in optimizing ligand density, scalability, and long-term stability, which hinder clinical translation. This review consolidates recent progress, compares emerging strategies, and highlights critical barriers to translation. By addressing current gaps in clinical application and proposing potential solutions, this work offers a forward-looking perspective on the future of multifunctional liposomal formulations in oncology. Ultimately, this review aims to guide future research toward safer, more effective, and patient-centered cancer therapies. • Liposomal DOX formulations enhance tumor targeting while reducing cardiotoxicity. • Functionalized liposomes with ligands improve specificity and overcome drug resistance. • Thermosensitive and pH-responsive liposomes enable precise drug release at tumor sites. • Scalability, cost, and regulatory hurdles remain key challenges to clinical translation.