Nanogel-Equipped CAR-T Cells Enhance Treatment of Solid Tumors

A team of researchers from the Changchun Institute of Applied Chemistry has developed a nanogel-based strategy to enhance the effectiveness of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors. The study focuses on overcoming a key barrier to CAR-T cell efficacy: the dense extracellular matrix (ECM) surrounding tumor tissues.

In solid tumors, the ECM restricts the infiltration of immune cells, limiting the antitumor activity of CAR-T therapies. Although hyaluronidase (HAase), an enzyme that breaks down ECM components, has shown potential in combination therapies, its low tumor accumulation has reduced therapeutic benefit. To address this issue, the researchers engineered CAR-T cells armed with HAase-loaded nanogels (H-NGs) that can degrade the ECM more efficiently.

Engineering nanogels for responsive enzyme release

The HAase-loaded nanogels were created using supramolecular polymer chains built through host–guest interactions between adamantane (Ad) and cyclodextrin (CD). Ad groups were chemically linked to polymer backbones using thioketal linkers, which degrade in environments with high levels of reactive oxygen species (ROS)—a hallmark of many tumor microenvironments (TME). This design enables the nanogels to disassemble and release HAase in response to ROS levels in the tumor.

To attach the nanogels to the CAR-T cells, the researchers used metabolic oligosaccharide engineering (MOE). This technique modified the surface of the CAR-T cells with azido-functional groups that enabled the stable conjugation of nanogels via click chemistry. The result is a CAR-T cell coated with HAase nanogels that can deliver the enzyme directly to the tumor site, enhancing ECM degradation and facilitating deeper immune cell penetration.

In vivo validation in solid tumor model

In preclinical studies using the Raji solid tumor model, CAR-T cells modified with H-NGs achieved significantly greater tumor inhibition than either free nanogels or unconjugated CAR-T cells. The H-NG CAR-T cells resulted in more extensive ECM degradation and an 83.2% tumor inhibition rate. This approach not only improved the physical infiltration of the CAR-T cells into the tumor core but also appeared to alter the immunosuppressive nature of the TME.

Molecular mechanisms and delivery strategy

To achieve selective release of HAase within the tumor, the nanogels were designed to respond to high ROS levels through two mechanisms: cleavage of the thioketal linker and degradation of phenylboronic acid (PBA) groups. This dual-response mechanism enables precise and localized enzyme release on the surface of the CAR-T cells.

The approach builds on earlier work by the team and introduces a pseudo-autocrine delivery system, where the HAase is released in proximity to the engineered immune cells. This delivery mechanism is intended to prevent premature enzyme degradation or clearance in circulation.

A strategy for improved delivery and ECM modulation

By combining CAR-T cell trafficking ability with nanogel-based enzyme delivery, the study presents a potential framework for enhancing the performance of CAR-T therapy in solid tumors. Although tested only in a mouse model, the findings support further exploration of this delivery strategy for clinical application.

Reference: Zhao H, Gao Y, Ma S, et al. Hyaluronidase nanogel-armed CAR-T cell for synergistically reducing tumor extracellular matrix and improving efficacy against solid tumors. Nano Res. 2025. doi: 10.26599/NR.2025.94907359 

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