CAR-T cell therapy has revolutionized cancer treatment, particularly for hematologic malignancies. Its success in achieving durable responses in refractory and relapsed cancers is undeniable. However, the clinical translation of CAR-T cells is hampered by significant adverse effects, including CRS, ICANS, OTOT, secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (sHLH/MAS), infectious susceptibility, coagulopathy, hematologic cytopenia, and latent human herpesvirus 6 reactivation. These adverse events, especially CRS, ICANS, and OTOT, pose significant clinical challenges. While strategies exist to mitigate these effects, balancing maximal cytotoxic potential with minimal side effects remains a major hurdle. Biomaterials offer a promising avenue to address this challenge due to their strong targeting capabilities, sustained release effects, enhanced bioavailability, controlled responsivity, substantial drug-loading capacity, multifunctionality, ease of manipulation and customization, and minimal toxicity. This review examines how biomaterials can be integrated into CAR-T cell therapy to improve safety and efficacy.

The review extensively cites literature on CAR-T therapy's efficacy and limitations. Numerous studies highlighting the success of CAR-T cell therapy in various cancers are referenced (e.g., refractory and relapsed CD19+ leukemia and lymphoma, BCMA+ multiple myeloma). Existing literature on the mechanisms and management of CRS, ICANS, and OTOT is reviewed, including the use of immunosuppressants like glucocorticoids and tocilizumab. The limitations of these existing treatments, such as adverse drug reactions and immunosuppression, are discussed. Furthermore, the existing literature on the use of various biomaterials in biomedical fields—inorganic and organic nanoparticles, synthetic materials, hydrogels, and 3D scaffolds—is reviewed, emphasizing their advantages for drug delivery and targeted therapies.

This review article employs a systematic literature search and analysis of existing research on CAR-T cell therapy and biomaterials. The authors examine the pathophysiological mechanisms of CRS, ICANS, and OTOT, drawing upon published studies on the roles of various cytokines and immune cells in these processes. They then discuss specific examples of biomaterial-based strategies designed to mitigate these toxicities. These examples include the use of IL-6-adsorbing hydrogels to neutralize excess IL-6 in CRS and the in situ PEGylation of CAR-T cells to reduce interactions with monocytes and macrophages. The review also analyzes strategies using biomaterials to control CAR-T activity and prevent OTOT, specifically focusing on photothermal sensitive switches incorporating HSPB1 and light-switchable CAR-T cells combined with upconversion nanoparticles. The methodology involves a comprehensive review of published studies, examining both the theoretical underpinnings and pre-clinical results of the discussed biomaterial approaches.

The review highlights several key strategies using biomaterials for enhancing CAR-T therapy safety: 1. **IL-6-adsorbing hydrogel (IL6S):** This temperature-sensitive hydrogel conjugated with IL-6 antibodies effectively captures excess IL-6, reducing CRS-related symptoms and mortality in preclinical models without impacting anti-tumor efficacy. However, limitations exist regarding in vivo degradation and clearance. 2. **In situ PEGylation of CAR-T cells:** This method involves modifying the CAR-T cell surface with polyethylene glycol (PEG) to hinder interactions with monocytes/macrophages, reducing cytokine release and alleviating CRS and ICANS. While effective in preclinical studies, pre-existing anti-PEG antibodies pose a significant challenge. 3. **Photothermal sensitive switch (HSPB1):** This approach uses a heat-sensitive switch incorporated into the CAR structure, allowing for precise control of CAR expression using near-infrared light and gold nanorods (AuNRs), enabling targeted activation of CAR-T cells at the tumor site while reducing OTOT. 4. **Light-switchable CAR-T cells (LiCAR-T):** This innovative strategy leverages upconversion nanoparticles (UCNPs) to activate CAR expression only under dual activation (blue light and tumor antigens), further enhancing the precision and safety of CAR-T cell therapy in pre-clinical models. The review also notes the potential for using focused ultrasound (FUS) to remotely control CAR-T cell activity, although currently no biomaterials are specifically designed for this purpose. The overall findings suggest that biomaterials offer versatile tools to manage the significant toxicities associated with CAR-T therapy, paving the way for safer and more effective treatment.

This review demonstrates that biomaterial-based strategies hold immense promise for mitigating the toxicities associated with CAR-T cell therapy. The successful application of these strategies in pre-clinical models suggests their potential for clinical translation and offers a significant advancement over current approaches relying primarily on systemic immunosuppression. However, several challenges remain, including the need for thorough safety evaluations in large animal models, assessing the impact of immunogenicity, and optimizing administration routes and dosages. The successful integration of stimuli-responsive materials and advanced gene-editing techniques with biomaterials would further enhance the precision and safety of CAR-T cell therapy. The expanding use of CAR-T therapy in autoimmune diseases underscores the importance of these safety improvements, and developing biomaterial strategies that can be employed across various clinical applications is a crucial area of future research.

The integration of biomaterials offers a paradigm shift in mitigating the adverse effects of CAR-T cell therapy. The strategies highlighted demonstrate the potential for enhanced precision, targeted control of CAR-T activity, and reduced off-target effects. Future research should focus on rigorous pre-clinical studies in large animal models, clinical trials, and collaborative efforts to fully realize the potential of biomaterial interventions in improving the safety and efficacy of CAR-T therapy. The ability to finely control CAR-T cell activation and reduce systemic inflammation holds immense promise for a wider and safer implementation of this revolutionary therapeutic approach.

This review focuses primarily on pre-clinical data. While promising, the translation of these findings into clinical practice requires further research and clinical trials to confirm efficacy and safety in humans. The potential immunogenicity of certain biomaterials, like PEG, needs further investigation. Also, the long-term effects of some biomaterial interventions remain unknown and warrant further research. The study primarily focuses on the use of biomaterials to reduce side effects in anti-tumor CAR-T cell therapy. Although the authors mention the expanding use of this therapy in autoimmune diseases, the application of the discussed biomaterials in such conditions requires further investigation.