Engineering Immunity: Liposomes as Smart Drug Delivery Agents

While cancer immunotherapy is an innovative therapy for malignant disease, it has associated problems like systemic toxicity and off-target effects. In the growing field of cancer treatment, there have been significant developments through the use of nanotechnology, with liposomes being one of its major components. This article reviews basic principles of cancer immunotherapy and the constituents of the TME, particularly the interaction between pro-tumor and anti-tumor immune cells. We present the established use of liposomes in cancer immunotherapy, particularly in encapsulating immunostimulatory components such as STING, TLR, and immune checkpoint inhibitors. The article then focuses on the more recent developments in engineering of liposomes with the focus on functionalization of moieties aimed at targeting cancer and tumor associated immune cells. Moreover, some of the most advanced developments like the hybridization of liposomes with cancer, red blood cell, and exosome membranes and the use of liposomes in therapies mediated by bacteria and oncolytic viruses are considered. 

Initially functioning as simple drug carriers, liposomes have evolved into intricate scaffolds for targeted therapeutics. This change occurred after their elucidation in the 1960s as phospholipid bilayer vesicles. They offer pliant, biocompatible, and non-immunogenic delivery systems capable of encapsulating diverse therapeutic agents such as TLR and STING immunotherapeutics, cancerous and autoimmune-targeting chemotherapeutics, adjuvants, and various other immunostimulatory constituents. For example, PEGylated forms of liposomes, such as Doxil, have shown enhanced circulation time and reduced systemic toxicity. More recently, custom-engineered liposomes have surfaced which enable cancerous cell or tumor-associated immune cell peptide or antibody-specific surface functionalization for precise targeting. pH-sensitive liposomes can deliver the immunomodulators to the tumor microenvironment (TME), augmenting the intratumoral immune cell infiltration and activation while preserving the surrounding healthy tissues. Tumor specificity is further achieved and circulation time prolonged by the incorporation of natural liposomal membranes derived from cancer cells, red blood cells, and exosomes, which mimic biological structures. Furthermore, liposomes have been incorporated into therapies based on baculoviral and oncolytic viral vectors to strengthen immunologic responses to enhance the immune contexture. These multifaceted approaches assist in breaching immune tolerance.

The use of liposome immunotherapy within the clinical practice is well developed as different formulations are tested or already approved for different types of cancer. Liposomes are interpreted for both hematological and solid tumors. This means that different immune microenvironments associated with these cancer types are recognized. Hematologic malignancies such as leukemia and lymphoma are more accessible to immune modulation by liposome therapy because they have easier access to immune effector cells. On the other hand, solid tumors are often difficult to treat due to their dense stroma and hypoxic cores, but liposome modifications such as pH sensitivity and enzyme-like release function can help overcome these challenges. Additionally, liposomes are tested in the context of T-cell therapeutics, such as expanding CAR-T cells by delivering stimulating factors and preventing T-cell fatigue. Clinical research has adopted liposomal vaccines and immune checkpoint inhibitors (ICIs) to improve efficacy and simultaneously control immune-related side effects. Liposomes promise accurate and personalized immunotherapy, but clinical integration challenges remain, including topics of patient response scaling, regulation and variation, which need to be considered for future research.

REFERENCE

Moghaddam SH, Vatankhah A, Oroojalian F, Kesharwani P, Sahebkar A. Liposomes as Immunotherapeutic Carriers: A Game-Changer in Cancer therapy. Journal of Drug Delivery Science and Technology. 2025 Mar 1;106847. Available from: https://doi.org/10.1016/j.jddst.2025.106847