Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers, but traditional approaches to ACT are poorly effective in treating solid tumors observed clinically. Novel delivery methods for therapeutic cells have shown promise for treatment of solid tumors when compared with standard intravenous administration methods, but the few reported approaches leverage biomaterials that are complex to manufacture and have primarily demonstrated applicability following tumor resection or in immune-privileged tissues. Here, we engineer simple-to-implement injectable hydrogels for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improve treatment of solid tumors. The unique architecture of this material simultaneously inhibits passive diffusion of entrapped cytokines and permits active motility of entrapped cells to enable long-term retention, viability, and activation of CAR-T cells. The generation of a transient inflammatory niche following administration affords sustained exposure of CAR-T cells, induces a tumor-reactive CAR-T phenotype, and improves efficacy of treatment.

Hydrogels that can be injected into the body using standard needles or catheters enable a minimally invasive strategy to prolong local delivery of therapeutic cargo. In particular, physically cross‐linked hydrogels exhibit shear‐thinning and self‐healing behaviors enabling facile injectability and depot formation upon administration. While prior efforts to characterize these systems have focused on injectability and cargo release behaviors, prediction of cargo release in the body often assumes these materials form a depot rather than spreading out upon administration. Here, it is evaluated how hydrogel rheology correlates with depot formation and persistence following subcutaneous administration in mice with two physiochemically distinct, physically cross‐linked hydrogel systems. Calcium‐alginate and polymer‐nanoparticle hydrogel systems exhibit variable mechanical behaviors across several rheological properties (stiffness, viscoelasticity, yield stress, and creep). By relating measured rheological properties to depot formation and persistence time following subcutaneous administration, it is identified that yield stress is predictive of initial depot formation while creep is predictive of depot persistence for these two gel systems. Indeed, only materials with yield stresses >25 Pa form robust depots, and reduced creep correlates with longer depot persistence. These findings provide predictive insights into design considerations for hydrogel technologies capable of extended controlled release of therapeutic cargo.

Adoptive cell therapy (ACT) has proven to be highly effective in treating blood cancers such as B cell malignancies, but traditional approaches to ACT are poorly effective in treating the multifarious solid tumors observed clinically. Locoregional cell delivery methods have shown promising results in treating solid tumors compared to standard intravenous delivery methods, but the approaches that have been described to date have several critical drawbacks ranging from complex manufacturing and poor modularity to challenging adminstration. In this work, we develop a simple-to-implement self-assembled and injectable hydrogel material for the controlled co-delivery of CAR-T cells and stimulatory cytokines that improves treatment of solid tumors. We evaluate a range of hydrogel formulations to optimize the creation of a transient inflammatory niche that affords sustained exposure of CAR-T cells and cytokines. This facile approach yields increased CAR-T cell expansion, induces a more tumor-reactive CAR-T phenotype, and improves efficacy in treating solid tumors in mice.

Composites of polymers and organized carbon nanotube (CNT) networks have been proposed as next-generation lightweight structural materials, yet polymer infiltration of CNT networks often results in stress-concentrating heterogeneities, due to local CNT aggregation or incomplete infiltration. Herein, it is demonstrated that dense CNT-polymer composites with tailored polymer distribution can be obtained by interfacial polymerization (IP), performed in situ within CNT networks. Three regimes of the in situ interfacial polymerization (ISIP) process are identified: a reaction-limited regime where the polymer forms beads on the CNTs; a uniformly-filled regime with polymer throughout the CNT network; and a transport-limited regime with polymer only near the outer surface of the network. Uniform polyamide-CNT composite sheets obtained by this method have a Young's modulus of 31 GPa and a tensile strength of 776 MPa, which is a twofold increase compared to the pristine CNT sheets. Premature failure of the composites is attributed to large voids in the pristine CNT sheets, suggesting that further improved mechanical properties can be achieved with a more homogeneous CNT network. Nevertheless, the rapid rate and overall controllability of ISIP suggest its viability for formation of polymers within CNT networks via roll-to-roll methods.

Hydrogels that can be injected into the body using standard needles or catheters enable a minimally invasive strategy to prolong local delivery of therapeutic drug and cellular cargo. In particular, physically crosslinked hydrogels exhibit shear-thinning and self-healing behaviors enabling facile injectability and depot formation upon administration. While prior efforts to characterize these systems have focused on injectability and cargo release behaviors, prediction of cargo release in the body often assumes the materials form a depot rather than spreading out upon administration. Here, we evaluate how hydrogel rheology correlates with depot formation and persistence following subcutaneous administration in mice with two physicochemically-distinct, physically crosslinked hydrogel systems. We evaluate calcium-alginate and polymer-nanoparticle hydrogel systems exhibiting variable mechanical behaviors across several rheological properties (stiffness, viscoelasticity, yield stress, and creep). By relating measured rheological properties to depot formation and persistence time following subcutaneous administration, we identify that yield stress is predictive of initial depot formation while creep is predictive of depot persistence. Indeed, only materials with yield stresses greater than 25 Pa form robust depots and reduced creep correlates with longer depot persistence. These findings provide predictive insights into design considerations for hydrogel technologies capable of extended controlled release of therapeutic cargo.