The applications of hydrogels have expanded significantly due to their versatile, highly tunable properties and breakthroughs in biomaterial technologies. In this review, we cover the major achievements and the potential of hydrogels in therapeutic applications, focusing primarily on two areas: emerging cell-based therapies and promising non-cell therapeutic modalities. Within the context of cell therapy, we discuss the capacity of hydrogels to overcome the existing translational challenges faced by mainstream cell therapy paradigms, provide a detailed discussion on the advantages and principal design considerations of hydrogels for boosting the efficacy of cell therapy, as well as list specific examples of their applications in different disease scenarios. We then explore the potential of hydrogels in drug delivery, physical intervention therapies, and other non-cell therapeutic areas (e.g., bioadhesives, artificial tissues, and biosensors), emphasizing their utility beyond mere delivery vehicles. Additionally, we complement our discussion on the latest progress and challenges in the clinical application of hydrogels and outline future research directions, particularly in terms of integration with advanced biomanufacturing technologies. This review aims to present a comprehensive view and critical insights into the design and selection of hydrogels for both cell therapy and non-cell therapies, tailored to meet the therapeutic requirements of diverse diseases and situations.

Introduction

The forefront of modern medical research has witnessed the emergence of innovative cell-based therapies (i.e., utilizing living cells as bioactive agents for disease treatment)^1,2,3 and various promising non-cell therapeutic modalities.^4,5,6 Despite their potential, these advanced therapeutic strategies still face significant hurdles in clinical translation.^1,7,8 In cell-based therapies, transplanted cells are particularly vulnerable to variations in the physiological and pathological conditions of the host, such as oxygen tension, pH levels, osmolality, nutritional availability, and intercellular signaling.^1,9 These environmental fluctuations may reduce cell survival and compromise their therapeutic functionalities, thereby diluting the efficacy of cell therapy.¹⁰ Moreover, the effective delivery of therapeutic cells presents another significant challenge, as illustrated by the frustrated homing and trafficking capabilities of natural killer (NK) cells.¹¹ Influenced by the circulatory and lymphatic systems as well as endogenous signaling, these cells often fail to sufficiently penetrate solid tumors, leading to suboptimal therapeutic outcomes.¹¹ Additionally, therapeutic cells may suffer from severe immune rejection and rapid clearance by the host’s immune systems, resulting in unsuccessful engraftment and failure to achieve desired therapeutic effects.

Non-cell therapeutic modalities, such as small molecule drug therapies, although less susceptible to environmental factors compared to living cell agents, still encounter many obstacles in clinical applications. These include unfavorable pharmacokinetics and low bioavailability with only a minor fraction of administered drugs reaching the bloodstream and effectively targeting the intended tissues or organs.⁸ Furthermore, systemic administration is often accompanied by undesirable adverse reactions,¹² possibly dampening the compliance of patients. Bioactive agents, like proteins or genes, are prone to inactivation, degradation, and rapid clearance in the complex and variable in vivo microenvironments,^13,14,15 substantially diminishing their therapeutic potential. Other non-cell therapeutic approaches, including physical intervention therapies, also face challenges in achieving selective targeting and effective treatment of deep tissues. To overcome these challenges, integration with other advanced technologies, particularly rapidly developed biomaterial technologies, appears to be a rational and feasible strategy for both cell- and non-cell therapeutics.

Hydrogels, which are highly hydrated three-dimensional (3D) polymeric matrices, hold substantial promise in medical and biomedical fields, owing to their excellent biocompatibility, chemical modifiability, and physical tunability, along with relatively straightforward processing procedures. These features position hydrogels as ideal platforms for both cell and non-cell therapy applications by fulfilling diverse requirements and significantly boosting therapeutic efficacy. Hydrogels have demonstrated potential in supporting cell viability and functionalities¹⁶ and in facilitating targeted delivery¹⁷ and controlled release of therapeutic agents.¹⁸ Therefore, the combination of hydrogels into cell- and non-cell therapeutics can not only ensure their therapeutic effectiveness and efficacy in vivo but also minimize systematic adverse effects,¹⁹ probably widening the therapeutic windows of these modalities.

Although early-generation hydrogels may exhibit limited flexibility due to their simplistic structures, restricting their applicability in complex therapeutic environments²⁰ and dynamic release-based therapeutic strategies,²¹ current synthesis and modification technologies have matured enough to advance this material significantly. For instance, a variety of responsive hydrogels has been developed to react to specific biological and pathological stimuli (e.g., pH,²² temperature,²³ reactive oxygen species (ROS),²⁴ and other exogenous stimuli) to meet the intricate requirements of specific diseases and escalating clinical demands. By tailoring their chemical compositions, crosslinking strategies, and physical structures,^25,26,27 newly developed hydrogels are equipped with versatile properties that allow them to directly regulate cellular behaviors, elicit specific cell phenotypes, and achieve controlled release and disease-specific targeting. As biomedical engineering technologies continue to evolve rapidly, driven by advances in cell therapy, immunotherapy, gene therapy, regenerative medicine, and a shift towards precision medicine, the applications of hydrogels are poised for further expansion.^28,29

This review aims to provide a comprehensive understanding of the advancements and clinical applications of hydrogels in the context of cell and non-cell therapies (Fig. 1). We begin with an overview of hydrogels and the commonly used responsive design modes, including temperature, pH, ROS, light, electric and magnetic fields (Fig. 2). Subsequently, we outline mainstream cell therapies (e.g., stem cell therapy and adoptive cell transfer (ACT) therapy), summarizing their current translational application challenges and exploring hydrogels’ role in overcoming these. We then discuss the advantages and design considerations of hydrogels tailored for cell-based therapeutics, with a focus on the factors influencing cell therapy’s efficacy, the pivotal role of hydrogels, and the design principles on their physicochemical properties. For non-cell therapies, we also explore the advantages of incorporating hydrogels and their design preferences in this context. Then, we examine hydrogels’ efficacy in drug delivery, including small molecules, peptides, proteins, and genes, and in physical intervention therapies such as photothermal (PTT), photodynamic (PDT), sonodynamic (SDT), and radiation (RT) therapy, as well as their utilities in other non-cell therapy domains to serve as adhesives, artificial tissues, and biosensors. Additionally, we also review the current applications of hydrogel-mediated cell and non-cell therapy in clinical trials and discuss ongoing challenges, intending to provide a snapshot for future clinical translational applications of hydrogels. Finally, we conclude by outlining emerging developments that leverage advanced biomanufacturing technologies with hydrogels to highlight their prospective research directions and challenges.