# Synthesis of Hydrogel-Based Microgels and Nanogels Toward Therapeutic and Biomedical Applications
## 5 Therapeutic and Biomedical Applications of Micro- and Nano-Hydrogels
### Anticancer Treatment  
Hydrogel-mediated anticancer therapies can be broadly classified into chemotherapy and immunotherapy. Chemotherapy remains a major cancer treatment method, by accompanying cytotoxic drugs to affect rapidly dividing tumor cells. Hydrogel-based drug delivery systems are expected to provide versatile platforms for improving the delivery and stability of chemotherapeutic agents while addressing several limitations of conventional therapies. The basis of the chemotherapeutic approach of hydrogels is the encapsulation of drugs within the hydrogel matrix to enhance their solubility and bioavailability and to prevent degradation. The conventional chemotherapeutic agents such as doxorubicin (DOX) or paclitaxel are classified as small molecules that function directly with nucleic acids or proteins within tumor cells, leading to apoptosis (Figure 6a) [250]. The effectiveness of these drugs is significantly limited when delivered intravenously, due to several pharmacokinetic and pharmacodynamic challenges. First, the non-specific distribution of drugs caused by poor tumor targeting often results in cytotoxic effects on healthy tissues and organs, also known as common side effects of chemotherapy, like damage to bone marrow, the gastrointestinal tract, and hair follicles. Second, molecular drugs generally exhibit a high clearance rate, either via renal excretion, hepatic metabolism, or bindings to serum proteins. Also, some of these agents are extremely hydrophobic and require solubilizing agents like ethoxylated castor oil (Cremophor(r) EL) or DMSO, which poses additional toxicity [100, 251, 252]. Incorporation of chemotherapeutic drugs into nanoscale hydrogels offers promising potential to overcome these challenges and to enhance the therapeutic efficacy. Their high-water content and tunable properties allow sustained and controlled drug release, mitigating the systemic toxicity. Also, nanogels could passively target tumor sites via the EPR effect, enabling the selective accumulation of drugs in tumor tissues. Encapsulation provides a physical boundary between the drugs and plasma, and it allows us to protect drugs from rapid clearance [8, 186]. Immunotherapy is another major classification of anticancer therapy, which harnesses the patient's immune system to recognize and eliminate cancer cells [253]. Unlike chemotherapy, which directly interacts with rapidly dividing cells, immunotherapy, as famously represented by the chimeric antigen receptor T cell (CAR T-cell) therapies, activates immune responses to achieve a more targeted and longer-lasting effect. To introduce major strategies, the checkpoint inhibitor utilizes the fact that the cancer cell exploits immune checkpoint pathways (PD-1/PD-L1, CTLA-4) to avoid T-cell activation and immune responses, and inhibits these pathways to suppress this mechanism. The cytokine-based approach utilizes signaling proteins, like interleukins or interferons, to boost immune response to cancer [11, 186, 254]. In adoptive cell therapy, such as CAR T therapy, the immune cells collected from a patient are rendered to enhance their anticancer activity. Thisprocess usually follows the collection of T-cells, genetic modification, cell expansion, and re-injection into the patient. The advantages of immunotherapy are prominent and highly expected to realize anticancer technologies with high-specificity, immunological memory, and minimal side effects. However, immune modulation requires careful considerations, including the risks of cytokine release syndrome (cytokine storm), graft vs. host diseases (GVHDs), neurologic immune-related adverse effects, collateral damage on off-target cells, and downregulation of tumor cells. [PERSON] et al. investigated a methacylated glycol chitosan (MGC) hydrogel system for post-surgical cancer therapy, aiming to combine sustained drug release and immunotherapy (Figure 6b). Chitosan was selected for its biocompatibility and pH-responsive properties and served as a scaffold for immune cell activation as well as a drug carrier.