Nanomaterials Mediated Enhancement of CAR-T for HCC: Revolutionizing Immunotherapy Strategies

Abstract

Hepatocellular carcinoma (HCC) presents significant challenges due to its aggressive nature and resistance to conventional treatments. While CAR-T therapy has shown promise in hematologic cancers, its application in HCC is limited by the tumor microenvironment (TME), insufficient T-cell infiltration, and antigenic heterogeneity. Nanomaterials offer a promising solution by enhancing CAR-T cell delivery, activation, persistence, and overcoming the immunosuppressive TME. This review focuses on the application of nanoparticles in CAR-T therapy, highlighting recent advancements in nanomaterials-based mRNA delivery, photothermal remodeling, and hydrogel platforms. Furthermore, nanomaterials-enhanced imaging tools enable real-time monitoring of CAR-T cell activity, improving therapeutic precision and safety. By addressing current limitations, nanomaterial-mediated CAR-T therapy holds the potential to transform HCC treatment, paving the way for more effective and personalized cancer immunotherapy.

Keywords: CAR-T; HCC; immunotherapy; nanomaterials; tumor microenvironment.

Figure 1

Mechanisms of nanomaterial-mediated TME modulation. Targeting immunosuppressive cells such as Tregs, MDSCs, and TAMs using nanoparticles offers a promising strategy to overcome the immunosuppressive TME, thereby enhancing the responsiveness of CAR-T cell therapy.

Figure 2

Flowchart for CRISPR/Cas9 integration with nanotechnology.

Figure 3

Nano-based mRNA CAR delivery in T cells. The LNP loaded with CAR mRNA induces T cells to express CAR, which results in tumor targeting and cell death.

Figure 4

Hydrogel for CAR T cells delivery.

Figure 5

Nanoparticle-assisted photothermal therapy enhances CAR-T cell infiltration. NIR-activated nanoparticles induce regional hyperthermia in tumors, promoting a favorable microenvironment for CAR-T cell infiltration and activity.