Nanotechnology-enhanced chimeric antigen receptor-T cell therapy for ovarian cancer
image: Created with Figdraw. LNP-based mRNA delivery enables safe, transient, and controllable protein expression with rapid kinetics and scalable production. However, challenges include immunogenicity, manufacturing complexity, and limited clinical validation. Promising applications include CAR-T cell engineering and ligand-directed targeting within the tumor microenvironment (TME). CAR, chimeric antigen receptor; LNP, Lipid Nanoparticles; mRNA, messenger RNA.
Credit: Ying Liu
CAR-T therapy for solid tumors faces challenges including immune evasion, suppressive microenvironment, and off-target toxicity. Nanotechnology—especially mRNA-loaded lipid nanoparticles (LNPs), hydrogels, and photothermal/acoustogenetic modulation—offers solutions. mRNA enables transient, safe CAR expression. LNPs can be engineered for targeted delivery. Preclinical ovarian cancer studies show promise (e.g., nfP2X7 CAR-T, multifunctional nanoparticles). This review highlights how nanotechnology enhances CAR-T safety, precision, and efficacy.
Introduction
Ovarian cancer is lethal due to late diagnosis and recurrence. CAR-T therapy succeeds in blood cancers but struggles in solid tumors. Nanotechnology provides innovative strategies: mRNA-based LNPs for transient CAR expression, biomaterial scaffolds, and external control systems.
mRNA-Based CAR-T Technologies
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Advantages: Non-integrating, tunable, rapid cell-free production, low immunogenicity.
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mRNA optimization: Codon usage, GC content, and secondary structure enhance stability/translation.
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LNPs: Composed of ionizable lipids, cholesterol, helper lipids, PEG-lipids; enable endosomal escape and organ targeting (e.g., siloxane-modified LNPs for lung/liver/spleen).
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Clinical progress: LNP-delivered CAR-mRNA shown feasible (2020). Acid-degradable LNPs improve release. Transient expression allows repeated dosing.
Hydrogels for Local Delivery
Injectable hydrogels (e.g., gelatin methacryloyl) form 3D scaffolds that support CAR-T cell viability, proliferation, and sustained release at tumor sites, often co-loaded with cytokines or checkpoint inhibitors.
Photothermal & Acoustogenetic Control
Near-infrared light triggers local hyperthermia (via polydopamine-coated nanoparticles), ablating tumors and enhancing CAR-T trafficking. Temperature-sensitive gene switches (40–42°C) enable localized expression of IL-15 or bispecific engagers. Focused ultrasound allows spatial control of CAR-T activation.
Application in Ovarian Cancer
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CAR-T target nfP2X7: Aberrant on ovarian cancer, restricted in normal tissues; shows potent preclinical activity.
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Nanoparticle combinations: Co-delivery of adavosertib+olaparib; HA-coated nanoparticles for CD44 targeting, ferroptosis, and MRI.
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Clinical trials: MUC16, mesothelin, FRα trials show modest responses; mRNA-LNP platform offers safer, more flexible alternative.
Challenges
Manufacturing complexity, PEG immunogenicity, regulatory uncertainty, high cost, and limited clinical data remain obstacles.
Conclusions
Nanotechnology significantly enhances CAR-T therapy for ovarian cancer by improving safety, local control, and precision. Further translational research is needed to overcome manufacturing and regulatory hurdles.
Full text
https://www.xiahepublishing.com/2996-3427/OnA-2025-00013
The study was recently published in the Oncology Advances.
Oncology Advances is dedicated to improving the diagnosis and treatment of human malignancies, advancing the understanding of molecular mechanisms underlying oncogenesis, and promoting translation from bench to bedside of oncological sciences. The aim of Oncology Advances is to publish peer-reviewed, high-quality articles in all aspects of translational and clinical studies on human cancers, as well as cutting-edge preclinical and clinical research of novel cancer therapies.
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