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Updated: Nov 3, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
PLGA nanodepots co-encapsulating prostratin and anti-CD25 enhance primary natural killer cell antiviral and antitumor
Elizabeth E Sweeney1, Preethi B Balakrishnan1, Allison B Powell2
1The George Washington Cancer Center, The George Washington University, Washington, DC 20052, USA.
Abstract:
Natural killer (NK) cells are attractive effector cells of the innate immune system against human immunodeficiency virus (HIV) and cancer. However, NK cell therapies are limited by the fact that target cells evade NK cells, for example, in latent reservoirs (in HIV) or through upregulation of inhibitory signals (in cancer). To address this limitation, we describe a biodegradable nanoparticle-based "priming" approach to enhance the cytotoxic efficacy of peripheral blood mononuclear cell-derived NK cells. We present poly(lactic-co-glycolic acid) (PLGA) nanodepots (NDs) that co-encapsulate prostratin, a latency-reversing agent, and anti-CD25 (aCD25), a cell surface binding antibody, to enhance primary NK cell function against HIV and cancer. We utilize a nanoemulsion synthesis scheme to encapsulate both prostratin and aCD25 within the PLGA NDs (termed Pro-aCD25-NDs). Physicochemical characterization studies of the NDs demonstrated that our synthesis scheme resulted in stable and monodisperse Pro-aCD25-NDs. The NDs successfully released both active prostratin and anti-CD25, and with controllable release kinetics. When Pro-aCD25-NDs were administered in an in vitro model of latent HIV and acute T cell leukemia using J-Lat 10.6 cells, the NDs were observed to prime J-Lat cells resulting in significantly increased NK cell-mediated cytotoxicity compared to free prostratin plus anti-CD25, and other controls. These findings demonstrate the feasibility of using our Pro-aCD25-NDs to prime target cells for enhancing the cytotoxicity of NK cells as antiviral or antitumor agents.
Insights
This study introduces nanoparticle drug delivery to enhance natural killer (NK) cell therapy. Biodegradable nanoparticles prime target cells, significantly boosting NK cell effectiveness against HIV and cancer.
Area of Science:
- Immunology
- Nanotechnology
- Biomedical Engineering
Background:
- Natural killer (NK) cells are crucial for innate immunity against viruses like HIV and cancers.
- Current NK cell therapies face challenges due to target cell evasion mechanisms.
- Developing strategies to overcome immune evasion is vital for effective NK cell-based treatments.
Purpose of the Study:
- To develop a nanoparticle-based priming approach to enhance NK cell cytotoxic efficacy.
- To co-encapsulate a latency-reversing agent (prostratin) and an antibody (anti-CD25) into biodegradable nanoparticles.
- To evaluate the enhanced NK cell function against targets relevant to HIV and cancer.
Main Methods:
- Poly(lactic-co-glycolic acid) (PLGA) nanodepots (NDs) were synthesized using a nanoemulsion scheme.
- Prostratin and anti-CD25 were encapsulated within PLGA NDs, creating Pro-aCD25-NDs.
- Physicochemical characterization confirmed ND stability, monodispersity, and controlled release of active agents.
- In vitro studies used J-Lat 10.6 cells to model latent HIV and T cell leukemia.
Main Results:
- Pro-aCD25-NDs demonstrated stable physicochemical properties and controllable release kinetics.
- The nanoparticles successfully released active prostratin and anti-CD25.
- Administration of Pro-aCD25-NDs in vitro resulted in primed target cells.
- Primed cells exhibited significantly increased NK cell-mediated cytotoxicity compared to controls.
Conclusions:
- Biodegradable PLGA nanodepots offer a feasible platform for co-delivering therapeutic agents.
- The Pro-aCD25-NDs effectively prime target cells, enhancing NK cell cytotoxicity.
- This approach shows promise for improving NK cell-based therapies against HIV and cancer.
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