# Biomolecule Conjugation Strategy for HAGM Cryogels to Create 3D Immune Niches that Induce Multifunctional T Cells

## TL;DR

This paper introduces a 3D biomaterial scaffold that activates T cells more effectively than traditional 2D methods, offering a new tool for cancer immunotherapy.

## Contribution

A post-cryogelation conjugation strategy for immune-activating biomolecules on HAGM cryogels, preserving scaffold injectability and biomolecule integrity.

## Key findings

- HAGM scaffolds induce higher levels of multifunctional T cells with a less exhausted phenotype compared to 2D cultures.
- The scaffolds retain up to 60% of highly proliferative T cells after injection.
- The conjugation strategy allows covalent attachment of biomolecules without exposing them to harmful conditions.

## Abstract

Recently,
biomaterials have emerged as tools to activate and expand
T cells in the context of cancer immunotherapy. Most designs accommodate
T cells with a stimulatory two-dimensional (2D) environment. In contrast,
three-dimensional (3D) scaffolds, mimicking the complex architecture
of the lymph node, have been shown to outperform 2D synthetic constructs,
resulting in a more optimal T-cell expansion and phenotype. Here,
we used injectable glycidyl methacrylated hyaluronic acid (HAGM)-based
cryogel scaffolds to create a modular biodegradable 3D stimulatory
immune niche. We developed a strategy to achieve highly specific and
efficient covalent linking of immune-activating biomolecules, such
as T-cell-activating peptide MHC complexes and antibodies, to HAGM
scaffolds without compromising the injectable properties of the cryogels.
Importantly, because our conjugation strategy is carried out postcryogelation,
biomolecules are not exposed to free radicals and freeze–thawing
cycles, facilitating highly reproducible covalent attachment. Our
scaffold potently activates human- and murine-T cells, inducing higher
levels of multifunctional T cells with a less exhausted phenotype
compared to 2D cultures. Following injections, HAGM scaffolds retain
up to 60% of highly proliferative T cells. In conclusion, our HAGM
scaffolds are an easily adaptable tool for robust T-cell activation,
thus further expanding the biomaterial-based immunotherapy toolbox.