# Synthesis of Hydrogel-Based Microgels and Nanogels Toward Therapeutic and Biomedical Applications
## 1 Introduction  
Hydrogel-based systems have emerged noticeably over the past decades, largely driven by their ability to mimic biological environments, tunable properties, and biocompatibility [1, 2, 3, 4]. Traditional drug delivery methods often require frequent administrations or high dosages, which can lead to systemic toxicity and inefficient therapeutic outcomes. Hydrogels have been highlighted as a promising material to enable controlled and localized drug release, significantly improving therapeutic efficacy while minimizing side effects. Their tunable physical and chemical properties make them highly adaptable to various clinical needs, supporting applications including sustained and stimuli-responsive drug release [5, 6, 7, 8, 9].  
One of the most compelling attributes of hydrogels is the similarity to biological tissues and their microenvironments, which allows them to integrate seamlessly into physiological settings. This makes hydrogels particularly effective for applications in oncology, immunotherapy, precision medicines, and regenerative medicines. By incorporating responsive functionality or tailoring permeability, hydrogels can precisely regulate mass transfer of drugs, degradation kinetics, or targetability [9, 10]. Additionally, their ability to stabilize delicate and fragile biomolecules, including proteins and nucleic acids, underscores their potential toward advanced therapeutic technologies [11, 12, 13, 14].  
Despite their promising potential, hydrogel-based drug delivery systems still face significant challenges, including their mechanical stability, limited drug loading efficiency, undesirable bioactivity, and more importantly, translational barriers from laboratory research to clinical applications [4, 15, 16]. Moreover, the integration of hydrogel systems intomultidisciplinary fields such as nanotechnology and molecular biology requires a robust understanding of the interplay between material science and biological systems.  
While hydrogels in bulk form have been extensively studied and reviewed [5; 6; 10; 16; 17; 18], their particulate forms, microgels and nanogels, remain underexplored. These types of hydrogels are designed as discrete particles at micro- and nanoscale dimensions and offer unique advantages including high surface area-to-volume ratio, enhanced permeability, and versatility in targeting specific cellular pathways. Furthermore, controlled synthesis methods for these systems are not comprehensively reviewed, leaving a gap between the growing interests from the diverse fields of research and the practical implications.  
This review addresses two objectives: to provide fundamentals of hydrogel as bioengineering materials and their engineering strategies, and to discuss effective and controllable synthesis strategies for microgels and nanogels. It aims to bridge the theoretical principles and practical translation into experimental processes, with emphasis on the complexity and controllability of fabrication strategies. This review illustrates the material properties of selected synthetic and natural hydrogels, and the progress through conventional bulk synthesis methods. Next, the detailed guidelines on fabricating microgels and nanogels, including the implantation of functional properties, are discussed. This review concludes with an exploration of the recent applications of particulate-formed hydrogels and potential directions. The goal of this review is to deliver a foundational explanation for new researchers, offering practical insights for synthesis and functionalization, and fostering innovative research in the expanding field of hydrogel particle-based drug delivery systems.