Advances in hyaluronic acid-based biomaterials: applications in cancer therapy, wound healing, and disease management

Abstract

Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan and is essential in biomedical research due to its distinct properties, compatibility with biological tissues, and functions in preserving tissue hydration, lubrication, and the integrity of the extracellular matrix, a significance recognized since 1934. Its capability to develop hydrogels and react to environmental factors has provided it a strong factor for drug delivery, tissue engineering, and wound healing uses. This review emphasizes the various biomedical uses of HA-based materials, focusing on their functions in cancer treatment, wound healing, inflammation control, antibacterial properties, and antioxidant functions. In cancer treatment, HA-functionalized nanoparticles improve the targeted drug delivery by using the additional presence of CD44 receptors in cancer cells. HA-based hydrogels have demonstrated significant potential in advancing wound healing by regulating inflammatory responses, enhancing angiogenesis, and participating in the extracellular matrix remodeling. Moreover, HA’s anti-inflammatory and antioxidant characteristics have been utilized in the treatment of chronic inflammatory conditions including osteoarthritis and inflammatory bowel disease. The recent developments in HA-based materials have also demonstrated their promise in antibacterial applications, diabetes control, and in treating cardiovascular and neurological conditions. The advancement of HA-based intelligent drug delivery systems and bioactive scaffolds is ongoing, presenting new treatment options for tissue repair and disease management. This review emphasizes the diverse functions of HA in both health and disease, showcasing its capacity to tackle various medical issues through cutting-edge biomedical applications.

Graphical Abstract

Introduction

Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan and exerts a vital function in the biomedical research due to its physicochemical characteristics. Separated in 1934 from bovine vitreous humor, it’s a straight-chain polysaccharide composed of D-glucuronic acid and N-acetyl-D-glucosamine [1]. Due to its high molecular weight (reaching up to 2 × 10⁷Da) and thick solutions, it is vital in extracellular matrix (ECM), supporting tissue hydration, lubrication, and structural integrity [2]. HA is widely present in vertebrates, with significant amounts located in the vitreous humor of the eye, synovial fluid, and umbilical cord [3]. Its compatibility with biological systems, ability to decompose, and lack of immune response make it perfect for biomedical uses such as delivering drugs [4].

The functions of HA are affected by molecular weight; HMW-HA demonstrates anti-inflammatory effects, whereas LMW-HA encourages inflammation [5]. Cell surface receptors such as CD44 and RHAMM play various roles, regulating adhesion, migration, and proliferation in the cellular activities [6]. The decomposition of HA by hyaluronidases leads to the production of oligosaccharides, which are known to affect wound healing, angiogenesis, and immune reactions [7]. Moreover, the formation of HA’s hydrogel and its responsiveness to pH and reactive oxygen species (ROS) position it as an appealing option for intelligent drug delivery systems and scaffolds for tissue regeneration [4].

In the recent times, HA-based materials have been thoroughly investigated for their promise in tackling various medical issues, such as cancer treatment, wound healing, inflammation control, and tissue regeneration. The HA-functionalized nanoparticles have been developed to improve the targeted transport of chemotherapy drugs to cancer cells, utilizing the overexpression of CD44 receptors found in various tumor types [8]. In wound healing, hydrogels made from HA have shown significant potential in supporting tissue repair by adjusting the inflammatory response, improving angiogenesis, and aiding ECM remodeling [9]. Moreover, HA’s function in managing oxidative stress and inflammation has been utilized in the therapy of chronic inflammatory conditions, including osteoarthritis and inflammatory bowel disease [10]. As studies persist in revealing the complex functions of HA in health and illness, its possibilities for biomedical uses continue to grow, presenting new paths for treatment and tissue engineering.

In the recent years, the application of green biomaterials in the field of medicine has significantly increased. Notably, among the biomaterials and naturally occurring ones as well as those with biological functions, HA has been significantly utilized for the development of delivery systems. Although there have been a number of reviews about the application of HA-based delivery systems for chemotherapy drugs [11], natural compounds [12, 13], genes [14], photothermal therapy [15], photodynamic therapy [16], immunotherapy [17] and other applications. However, there is a need for an updated review to further demonstrate the application of HA in the different medicine fields and provide a state-of-art review. Moreover, the present review will highlight the bridge between chemistry and biology for improving application of HA in disease therapy.

This review fills critical gaps left by earlier fragmented and outdated reports by providing a state-of-the-art, multidisciplinary synthesis of HA applications across cancer therapy, wound healing, inflammation regulation, antibacterial and antioxidant applications, and chronic diseases. Unlike prior reviews that focused on single therapeutic areas or limited drug delivery roles, it integrates the recent advances in intelligent HA-based hydrogels, multifunctional nanostructures, and bioresponsive scaffolds, highlighting how chemical modifications translate into enhanced biological effects. By reframing HA from a passive scaffold to an active therapeutic platform with combined regenerative, anti-inflammatory, antibacterial, and antioxidant functions, the review emphasizes its potential for the clinical translation and highlights its significance as a versatile material at the interface of chemistry, biology, and medicine.

Hyaluronic acid: basics and principles

HA is a linear, unbranched polysaccharide comprised of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine [8], with a molecular weight that can reach up to 2 × 0⁷Da. In 1934, Karl Meyer and John Palmer first extracted it from the vitreous humor of a cow’s eye, but its structure was elucidated two decades later in 1970 by Laurent [1, 3]. Balazs [18] suggested “hyaluronan” in 1986 as a substitute for “hyaluronic acid,” emphasizing its ionization at physiological pH and attraction to cations. This molecule is prevalent in bacteria and vertebrates, particularly in the embryonic tissues and soft connective tissues in adults, occurring in abundance in the vitreous body of the eye and the umbilical cord [2]. HA, because of its carboxyl groups, carries a negative charge and demonstrates strong hydrophilicity, forming a viscous network at elevated molecular weights. Its physical and chemical characteristics assist in hydrating the ECM, preserving tissue balance, and withstanding compressive forces. HA engages with proteoglycans such as aggrecan to develop large molecular complexes, reinforcing the structure of the matrix. Moreover, HA develops a pericellular layer surrounding cells, affecting cell adhesion, movement, and growth, and acts as a lubricant in synovial fluid [2]. As a result, HA plays a vital role in various physiological and pathological conditions [7]. HA is mainly produced by extracting it from rooster combs or through recombinant techniques involving Streptococcus, with both methods resulting in materials that demonstrate varying rheological characteristics. In animals, HA is generated at the surfaces of fibroblast cells and engages with the CD-44 receptor within the ECM. Fibroblasts also produce hyaluronidase, which helps in the decomposition of HA, leading to smaller polymers made up of different dimeric chains. Although several fragments affect wound healing, the majority of HA-related effects are associated with a particular range of short-chain or long-chain products [5].

In 1979, Balazs created the first pharmaceutical-grade HA by developing a successful method for isolating and purifying the polymer from rooster combs and human umbilical cords. Balazs’ approach laid the foundation for the industrial production of HA. Since the early 1980s, HA has been extensively studied as a raw material for creating intraocular lenses for implantation, becoming an essential product in ophthalmology due to its safety and protective effects on the corneal endothelium. Additionally, HA has shown benefits in managing joint and skin issues, promoting wound healing, and enhancing soft tissue augmentation. Since the late 1980s, HA has been utilized in creating drug delivery systems, with ongoing efforts to develop HA-based carriers to improve therapeutic effectiveness. During the 1990s and 2000s, significant focus was placed on discovering and describing the enzymes that play a role in hyaluronic acid metabolism, alongside the development of bacterial fermentation techniques to produce hyaluronic acid with controlled size and polydispersity. At present, HA is a crucial compound employed in various medical, pharmaceutical, nutritional, and cosmetic fields. As a result, hyaluronic acid continues to be thoroughly researched to clarify its biosynthetic pathways and molecular biology, enhance its biotechnological production, create derivatives with better features, and increase its medical and cosmetic uses [4]. HA is essential for creating a hydrated network with collagen fibers, particularly in the vitreous humor, where it serves as an organizing nucleus in the intercellular matrix. It arranges cartilage glycoconjugates into intricate aggregates and is found in the pericellular coat encasing unfertilized ova and different cell types. Alterations in HA metabolism and activity have been associated with various diseases, such as arthritis and cancer. HA is utilized medicinally, featuring sodium hyaluronate for osteoarthritis therapy and its role as an ophthalmic agent in ophthalmology, taking advantage of its various molecular weights for distinct therapeutic outcomes [19].

HA receptors are essential in numerous biological functions apart from HA degradation, such as cellular aggregation, communication between cells and matrix, signaling from matrix to cells, and cell migration. Cellular aggregation happens when one HA molecule connects two cells through receptors, aided by high molecular weight HA (HMWHA) and obstructed by low molecular weight HA (LMWHA). The main HA surface receptors are CD44 and RHAMM. CD44, the initially recognized, is extensively found in fibroblasts, blood cells, and cancer cells, with its messenger RNA (mRNA) undergoing alternative splicing. RHAMM is widely expressed as well, promoting cell movement and the turnover of focal adhesions during migration and in response to cytokines [6]. The upcoming sections emphasize the use of HA in disease treatment and its biomedical application.

Biomedical application of hyaluronic acid-based materials

Cancer therapy

Cancer remains among the top causes of mortality globally. There are various issues in cancer treatment, such as immune evasion (and also using strategies to improve cancer immunotherapy) [20, 21] and resistance to chemotherapy [22]. Consequently, the research has concentrated on the incorporation of nanoparticles, which show potential in tumor suppression [23]. The incorporation of suberoylanilide hydroxamic acid (SAHA) into hyaluronic acid-functionalized F127 micelles enhances its delivery, cytotoxic efficacy, and tumor penetration in models of endometrial cancer. Moreover, 3D models show improved performance and CD44-targeted retention of nanoparticles, highlighting their ability to impede cell proliferation and mitigate EMT-related phenotypes [24]. HA, polyethylene glycol (PEG), and adipic dihydrazide (ADH) modified functionalized AuNPs were created as carriers for the antitumor agent doxorubicin (DOX), leading to a biocompatible nanocomposite (AuNPs@MPA-PEG-HA-ADH-Dox) that demonstrated uniform dispersibility and reduced cytotoxicity, while providing improved antitumor activity through CD44 receptor targeting in HepG2 and HCT-116 cell lines. The nanocomposite induced apoptosis by increasing ROS production, modifying mitochondrial membrane potential, and enabling real-time cell imaging, highlighting its potential as a theragnostic agent for colon cancer treatment [25]. Nano-sized assemblies made of amphiphilic iodinated hyaluronic acid (HA-TIBA) were developed for cancer diagnosis and therapy, enabling tumor-specific delivery of DOX while demonstrating enhanced cellular uptake and antitumor effectiveness in CD44-positive SCC7 cells via HA-CD44 receptor interactions. The HA-TIBA nanoassembly, combined with NIRF and CT imaging methods, showed improved tumor targeting and increased treatment efficacy in vivo, highlighting its potential as a theranostic nanosystem for CD44-expressing cancers [26]. Hyaluronic acid-dopamine conjugate-based sodium selenite-crosslinked hydrogels, containing indocyanine green, were developed for targeted breast cancer therapy, demonstrating biocompatibility, prolonged drug release, pro-oxidant actions, and efficient tumor growth inhibition without systemic toxicity (Fig. 1) [27].

Fig. 1. In Vivo Anticancer Efficacy, Body Weight Monitoring, and Thermal Profiles of Different Treatment Groups in MDA-MB-231 Tumor-Bearing Mice.

A–F An in vivo anticancer efficacy study was carried out using a mouse model bearing MDA-MB-231 tumors. Nine experimental groups were included: control, HD, HD + NIR laser, Se/ICG, Se/ICG + NIR laser, HD/Se, HD/ICG + NIR laser, HD/Se/ICG, and HD/Se/ICG + NIR laser. Tumor volume changes were tracked and expressed as mean ± SD based on five animals per group. Statistical differences were marked as follows: #p < 0.05 versus control; ^p < 0.05 versus HD; ^^p < 0.05 versus HD + NIR laser; /p < 0.05 versus Se/ICG; //p < 0.05 versus Se/ICG + NIR laser; and p < 0.05 versus HD/Se; %%p < 0.05 versus HD/ICG + NIR laser; and *p < 0.05 versus HD/Se/ICG. Body weight progression was also monitored for all nine groups and reported as mean ± SD (n = 5). Thermal profiles during both the initial and final laser irradiation sessions were documented for HD + NIR laser, Se/ICG + NIR laser, HD/ICG + NIR laser, and HD/Se/ICG + NIR laser groups. At the end of treatment, excised tumor weights were compared across all groups, and representative images of harvested tumors were captured for visual assessment. Histopathological examinations using hematoxylin and eosin (H&E) staining, along with TUNEL assays, were conducted on tumor samples from each group. A yellow 100 μm scale bar was included in the images. Overall, the evaluation encompassed therapeutic efficacy, thermal responses, tumor growth suppression, and histological changes. Reprinted with permission from Elsevier [27]

A novel combination of HA-DH was created to overcome the shortcomings of dihydroartemisinin (DHA), such as poor bioavailability and insufficient water solubility, with successful characterization confirming its nanoparticle formation and improved properties. The HA-DHA nanoparticles exhibited significant cytotoxic effects on lung cancer cells (A549), as shown by apoptosis assays, ROS production, and the depletion of mitochondrial membrane potential, highlighting the ability of hyaluronic acid conjugates to enhance the efficacy of anticancer treatments [28]. rtesunate (AS) slows tumor progression by increasing oxidative stress; however, its effectiveness is limited due to the insufficient availability of ferrous ions in tumors. To address this, AS/glucose oxidase (GOD) @HAZnO NPs were developed that utilize the interaction between hyaluronic acid and CD44 receptors to improve cellular uptake. Dynamic light scattering (DLS) and transmission electron microscope (TEM) confirmed the nanoparticles’ nanoscale size (~160 nm) and spherical shape. These nanoparticles demonstrate acid-sensitive degradation, enabling as much as 80% drug release in acidic conditions, compared to merely 20% in neutral environments. Cellular and in vivo research indicated that the combined delivery of AS and GOD via HAZnO nanoparticles significantly boosts ROS production, restricts glucose access for tumor cells, and effectively induces apoptosis and tumor suppression [29]. The increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases in cancer cells leads to higher levels of intracellular ROS, which supports survival and lessens radiation sensitivity. To tackle this, a CD44-specific hyaluronic acid nanoparticle containing the NOX inhibitor GKT831 was created (HANP/GKT831). This formulation demonstrated improved suppression of ROS production and tumor progression in comparison to GKT831 by itself. When given systemically, HANP/GKT831 honed in on breast cancer PDX tumors in mice, resulting in enhanced tumor suppression when used alongside low-dose localized radiation (Fig. 2) [30].

Fig. 2.

HANP/GKT831 acts by directly inhibiting NOX1 and NOX4, which lowers ROS levels in cancer cells and helps restore redox balance, a factor often linked to treatment resistance. By downregulating DNA repair genes and interfering with oncogenic pathways, including PI3K/AKT, WNT, and TGF-β, it increases tumor cell sensitivity to radiation-induced DNA damage and promotes apoptosis, thereby enhancing radiotherapy outcomes. When administered systemically, it localizes to tumors via CD44 targeting and enables intracellular drug release. Reproduced with authorization from ACS [30]

Blocking programmed Cell Death Ligand 1 (PD-L1) on tumor and dendritic cells promotes the production of tumor-reactive T lymphocytes, strengthening anti-tumor immunity. A polymeric nanoconjugate (PEG-HA-OVA/PPLs) was created using siPD-L1 polyplexes, PEGylated hyaluronic acid, and ovalbumin. PEG-HA-OVA/PPLs were simultaneously delivered to CD44^high tumor cells and CD44^high dendritic cells, promoting efficient cross-presentation of OVA and the reduction of PD-L1 in both cell kinds. This nanoconjugate not only facilitated the effective elimination of external tumor cells by OVA-specific T cells but also altered tumor microenvironment (TME) to stimulate strong T-cell responses against internal tumor antigens, leading to lasting protective immunity [31]. Chitosan-hyaluronic acid nanoparticles (GCHN) containing Gd-DTPA were developed as magnetic resonance imaging (MRI) contrast agents, displaying a spherical form, increased signal intensity, prolonged imaging time in tumor-bearing subjects, and minimal toxicity, making them a feasible choice for tumor identification [32]. A nanocomposite was developed employing a reduced polyanionic cluster (rP2W18) as a core carrier, which attaches DOX via ionic interactions and is surrounded by hyaluronic acid-grafted β-cyclodextrin to reduce toxicity and enhance targeting. When stimulated by a near-infrared (NIR)-II laser, the system achieves combined photothermal, chemotherapeutic, and chemodynamic effects, enabling controlled release of DOX and the generation of ROS within the tumor microenvironment [33]. A multifunctional nanostructure (CuS(DOX)-GO-HA) was developed for chemo-phototherapy, incorporating two photothermal agents (CuS and GO), a DOX, and a targeting component (HA). The approach demonstrated targeted internalization in CD44-overexpressing cancer cells, regulated drug release, enhanced photothermal effects, and efficient ROS generation, leading to significant tumor growth inhibition and favorable biodistribution, suggesting potential for future clinical applications [34]. Nanoparticles utilizing hyaluronic acid–ceramide (HACE), combined with (3-aminomethylphenyl) boronic acid (AMPB) and loaded with manassantin B (MB), were developed for directed tumor delivery. The coupling of AMPB to HACE resulted in the formation of HACE-AMPB/MB nanoparticles, which measure 239 nm and demonstrate high encapsulation efficiency. The AMPB on the surface boosted interactions with sialic acid in cancer cells, resulting in better uptake and effectiveness in CD44-positive MDA-MB-231 breast cancer cells through receptor-mediated endocytosis. In vivo experiments demonstrated better tumor targeting and therapeutic outcomes than HACE/MB nanoparticles, due to a combination of passive and active targeting mechanisms (Fig. 3) [35]. HA-coated superparamagnetic iron oxide nanoparticles (SPIONs), comprising HA-SPIONs and HA-PEG10-SPIONs, were developed for targeted cancer therapy and MRI-guided hyperthermia. The nanoparticles, which were 149 nm and 176 nm in size, demonstrated specific targeting of CD44, compatibility with biological systems, and efficient heating when exposed to an AMF. In vivo MRI showed better contrast with HA-SPIONs (40% T2 reduction) than with HA-PEG10-SPIONs (20%) in mice bearing SCC7 tumors. Alternating magnetic field (AMF)-induced hyperthermia significantly reduced cell viability ( < 40%) in SCC7 cells, supporting their potential for future cancer treatment research [36]. Consequently, growing evidence suggests that HA-based materials hold great potential in cancer treatment [37–43].

Fig. 3.

Schematic showing how HACE-AMPB/MB nanoparticles are used for tumor targeting and infiltration. Reprinted with permission from Elsevier [35]

A natural polysaccharide-based nanoplatform (TDTD@UA/HA micelles) was engineered to address multidrug resistance (MDR) in cancer by co-delivering ursolic acid (UA) and DOX. The micelles, around 140 nm in diameter, demonstrated significant drug-loading efficiency and were absorbed by tumor cells by hyaluronic acid (HA)-mediated uptake. Subsequent to cellular entrance, HA breakdown revealed triphenylphosphine groups, facilitating mitochondrial accumulation, where ROS induced the release of UA and DOX. Consequently, significant mitochondrial impairment occurred, characterized by ROS formation, membrane potential dissipation, and energy production disruption, finally resulting in the reinstatement of drug sensitivity in resistant MCF-7/ADR cells. Significant anticancer benefits were noted in vivo with minimal toxicity, suggesting considerable promise for this nanoplatform in multidrug-resistant tumor treatment [44]. Two novel nanoplatform-based approaches were delineated to augment cancer treatment by refining medication targeting and surmounting resistance. In hepatocellular carcinoma (HCC), a homologous cell membrane and hyaluronic acid-based nanocarrier (HMCLPs) was engineered to facilitate the regulated release of celastrol (CeT), enhancing bioavailability and minimizing toxicity [45]. HMCLPs markedly elevated ROS generation, caused mitochondrial impairment, and initiated apoptosis, leading to successful HCC therapy with few adverse effects. In an alternative method, hyaluronic acid nanoparticles containing the NOX1/4 inhibitor GKT831 (HANP/GKT831) shown the ability to reduce mitochondrial ROS, glycolysis, and oxidative phosphorylation in tumor cells, thereby hindering proliferation and invasion. In conjunction with radiation, HANP/GKT831 increased DNA damage, facilitated apoptosis, diminished immunosuppressive cells, and elicited cytotoxic immune responses, resulting in an 84.7% decrease in tumor growth in a colorectal cancer model [46]. Collectively, these results underscore the potential of nanocarrier-mediated therapeutics to enhance effectiveness, diminish toxicity, and improve treatment outcomes in cancer.

Beyond the aspects already discussed, further exploration of HA in cancer therapy could focus on its potential in modulating the TME, such as remodeling ECM stiffness, regulating immune cell infiltration, and alleviating hypoxia to enhance therapeutic response. HA-based systems could also be investigated as co-delivery platforms for multiple therapeutic agents, including combinations of chemotherapy, immunotherapy, gene therapy, and radiotherapy sensitizers, to overcome multidrug resistance. Additionally, exploiting HA’s natural biocompatibility and receptor specificity may advance the design of personalized, stimuli-responsive drug delivery systems that respond to tumor-specific triggers (pH, enzymes, ROS). Moreover, HA conjugates could be tailored for cancer stem cell targeting to prevent relapse and metastasis, while integrating HA with next-generation imaging modalities (such as multimodal PET/MRI or real-time optical tracking) could open new avenues for theranostics. Finally, the development of HA-based scaffolds for cancer-on-a-chip models may provide innovative preclinical platforms to better predict therapeutic outcomes.

Wound healing

A novel granular gel made of HA-LA showing ROS scavenging and antibacterial properties was developed to improve wound healing, particularly in diabetic patients. The extrudable, shear-thinning, and self-repairing gel effectively reduces chronic inflammation, eliminates excess reactive oxygen species, and improves tissue regeneration, showing significant potential for therapeutic application [47]. On day 7, the healing percentages for HA gel (84.4 ± 9.2%) and HA film (74.0 ± 15.0%) were markedly higher than those of the control group (51.7 ± 16.9%), with P-values of < 0.001 and 0.002. On day 7, the HA film demonstrated significant decreases in inflammation (P = 0.038) and improved re-epithelialization (P = 0.011); both HA groups exhibited reduced alpha 1 type I collagen (COL1α1) expression on day 3 compared to controls [48]. A straightforward method was employed to synthesize a water-soluble HA-Q compound, aimed at assessing its effectiveness in wound healing. The successful attachment of quercetin to the HA backbone, achieving a conjugation rate of 44.7%, was confirmed through FTIR, UV-Vis, and NMR spectroscopy. The resulting HA-Q mixture demonstrated enhanced water solubility, allowing for the preparation of a 20 mg/ml solution. It exhibited considerable biocompatibility, promoting the growth and movement of skin fibroblast cells, and displayed enhanced radical scavenging effectiveness compared to quercetin alone [49]. Paeoniflorin (PF), extracted from Paeonia lactiflora, encourages macrophages to shift from proinflammatory M1 to prohealing M2, improving diabetic wound healing in research. An HA-based hydrogel (HA-PF) enhances wound healing by diminishing inflammation and promoting angiogenesis, re-epithelialization, and collagen deposition, indicating potential clinical applications (Fig. 4) [9].

Fig. 4.

A hyaluronic acid–based hydrogel loaded with paeoniflorin (HA-PF) promotes diabetic wound repair by modulating macrophage activity. Reprinted with permission from Elsevier [9]

A versatile nanomedicine, HA@Cur/Cu, was developed to address chronic over-oxidation, inflammation, and bacterial infection, key factors that hinder timely wound healing in diabetes. Nanomedicine enhances curcumin’s bioavailability, enables controlled drug release, effectively prevents bacterial growth, reduces reactive oxygen species, and regulates inflammatory mediators, significantly improving diabetic wound healing in mice [50]. The developed dressing exhibits injectability, self-healing properties, and antibacterial features, with NaCl-triggered dissolution happening as required due to the disruption of electrostatic bonds. When applied to full-thickness wounds, it accelerates healing by effectively removing bacteria, reducing inflammation, increasing collagen formation, promoting keratinocyte movement, and improving angiogenesis, due to its strong adhesion, effective hemostatic characteristics, and powerful antibacterial activity [51]. Electro-responsive click-hydrogels created from hyaluronic acid (clickHA) and PEG, semi-interpenetrated with the conductive polymer PEDOT-MeOH, exhibited enhanced porosity, mechanical strength, and electrochemical activity, making them well-suited for skin wound healing. The biocompatible hydrogel promoted swift migration of epithelial cells and efficient wound healing through electrostimulation, closing a wound gap in one hour and creating a consistent cell monolayer [52]. A multifunctional bioadhesive hydrogel was developed using dynamic covalent bonding and light-activated bonding with oxidized hyaluronic acid, methacrylated gelatin, and bacteriocin JC. It showed an adhesive strength of 180 kPa, outperforming fibrin glue by 4.35 times. The hydrogel exhibited strong platelet adhesion, procoagulant properties, and enhanced hemostatic efficacy in a murine liver damage model. In diabetic mice, it reduced bacterial load, promoted M2 macrophage polarization, reduced inflammation, and accelerated wound healing (Fig. 5) [53].

Fig. 5.

Diagram depicting the wound-healing stages, inflammation, proliferation, and remodelling, emphasizing the impacts of UV radiation, Schiff base, and Jileicin under diabetic conditions. Reprinted with permission from ACS [53]

A hydrogel responsive to temperature, made from poloxamer, chitosan, and hyaluronic acid, loaded with dihydromyricetin, was developed, showing sustained drug release, biocompatibility, and antioxidant and anti-inflammatory properties. The hydrogel promoted skin healing in vivo by enhancing growth factor expression and reducing inflammation [54]. A microneedle made of HA combined with cerium/zinc-based nanomaterial (ZCO) is developed to tackle chronic diabetic wounds by neutralizing ROS, showing antibacterial and anti-inflammatory effects, and promoting angiogenesis and cell growth via the NF-κB pathway. In vivo studies using diabetic mouse models demonstrate that the ZCO-HA microneedle enhances wound healing without causing systemic toxicity, and RNA sequencing confirms its role in facilitating cell migration, reducing inflammation, and mitigating oxidative damage [55]. A hybrid HA-PU cryogel featuring a macroporous structure was created through self-initiated cross-linking, showcasing rapid shape restoration, fast hemostatic capabilities, and excellent biocompatibility, making it ideal for minimally invasive surgeries and wound healing uses. In vivo studies have demonstrated that the cryogel promotes hemostasis, decreases inflammation, and enhances tissue regeneration [56]. Supramolecular HA hydrogels, formed via non-covalent host-guest interactions between HA-cyclodextrin and HA-adamantane, demonstrated improved corneal wound healing by promoting cell adhesion, reducing inflammation, and mitigating corneal edema when compared to linear HA or untreated controls. These biocompatible, shear-thinning hydrogels show potential as an effective in situ therapeutic membrane for the repair and regeneration of the cornea [57]. A scaffold made of un and hyaluronic acid featuring an SDF-1-mimic peptide (Cx-HA + SMP) was created to enhance wound healing through stem cells. It gradually released SMP, enhancing stem cell migration, collagen synthesis, and tissue repair while minimizing scarring, surpassing Cx-HA + SDF-1 in effectiveness for wound healing (Fig. 6) [58].

Fig. 6.

The schematic depicts in-situ wound healing mediated by endogenous stem cells, initiated through the release of an SDF-1-mimicking peptide (SMP) from a click-crosslinked hyaluronic acid scaffold (Cx-HA + SMP). Reprinted with permission from Elsevier [58]

A thermoreversible injectable hydrogel was created for chronic wound care, exhibiting self-healing, moisture retention, and antibacterial characteristics. Consisting of hyaluronic acid and kappa-carrageenan, it showed thermal stability, customizable gelation, and prolonged release of meropenem (96.12% in PBS and 94.73% in wound fluid over a 24 h period). Antibacterial evaluations demonstrated considerable efficacy against P. aeruginosa, S. aureus, and E. coli. In vivo research conducted on SD rats showed a 90% rate of wound closure with the hydrogel, whereas other treatments achieved 70% and 60% respectively [59]. The effects of iontophoresis, HA, and GNPs were studied in a rat excisional wound model. A reduction in pro-inflammatory cytokines (IFNγ, IL-1β, TNFα, IL-6) and markers of oxidative stress (DCF, nitrite, carbonyl, sulfhydryl) was observed in the group receiving combination treatment (EW + MC + HA + GNPs). Levels of anti-inflammatory cytokines (IL-4, IL-10), growth factors (FGF, TGF-β), and antioxidant defense (GSH) increased, while SOD levels were reduced. Histological analysis showed a reduction in inflammatory infiltration in groups treated with MC therapy and combination therapy. The rates of wound contraction were heightened in all treatment groups compared to the control, demonstrating the effectiveness of the treatments in promoting epithelial healing. The tissue repair process showed significant enhancement with combination therapy compared to individual treatments [60]. A hydrogel with multiple functions is created by synthesizing quaternized chitosan, tannic acid, and oxidized hyaluronic acid through dynamic interactions. This injectable hydrogel, which possesses self-healing, antibacterial, and antioxidative qualities, improves free radical removal and supports angiogenesis, suggesting its potential effectiveness in speeding up wound healing for chronic bacterial infections and non-healing wounds [61]. Consequently, growing evidence shows the role of HA-based materials in promoting wound healing [62–68].

The advancement of multifunctional wound adhesives is essential in clinical practice, since few dressings offer both robust adhesion and efficient protection against infections from drug-resistant bacteria. Polysaccharide- and gelatin-derived hydrogels are esteemed for their biocompatibility and bioactivity, facilitating tissue regeneration. A multifunctional bioadhesive hydrogel has been developed via dynamic covalent bonding and light-activated covalent bonding, including oxidized hyaluronic acid, methacrylated gelatin, and the novel bacteriocin jileicin (JC). The hydrogel demonstrated an adhesive strength of 180 kPa, surpassing fibrin glue by a factor of 4.35. It exhibited robust platelet adhesion, procoagulant activity, and exceptional hemostatic efficacy in a murine liver damage model. The integration of JC enhanced macrophage phagocytosis and bactericidal efficacy. The combined immunomodulatory and bacterial membrane-disrupting effects facilitated effective activity against methicillin-resistant Staphylococcus aureus. In investigations of wound healing involving diabetic mice with infected full-thickness skin defects, the hydrogel markedly decreased bacterial load, facilitated M2 macrophage polarization, mitigated inflammation, and expedited tissue restoration. The hydrogel, characterized by superior biocompatibility, antibacterial properties, and adjustable adherence, serves as a viable therapeutic platform for the management of infected skin lesions [53]. Diabetic wound healing is impeded by inflammation, infection, oxidative stress, and protracted tissue repair, rendering improved dressings indispensable. Adhesive, injectable, and self-healing wound dressings (HA-DA/PRP) were created by integrating dopamine-modified hyaluronic acid with platelet-rich plasma. These dressings exhibited robust tissue adhesion, fast self-repair, and adaptation to irregular wounds, while enhancing fibroblast proliferation and migration, mitigating oxidative stress and inflammation, and displaying antibacterial properties against both gram-positive and gram-negative bacteria. In vivo, they expedited diabetic wound healing by inhibiting bacterial proliferation, promoting granulation tissue development, facilitating neovascularization, increasing collagen deposition, and altering macrophage polarization from M1 to M2. HA-DA/PRP together presents a potential approach for the management of the microenvironment and the enhancement of diabetic wound treatment [69].

Inflammation regulation

Oxidative stress along with inflammation plays a major role in causing tissue damage. (–)-epigallocatechin-3-gallate (EGCG) is recognized for its antioxidant and anti-inflammatory attributes, positioning it as a possible therapy for tissue degeneration. This research presents an injectable hydrogel depot, EGCG HYPOT, developed through the phenylborate ester reaction between EGCG and PBA. Consisting of PBA-modified methacrylated hyaluronic acid (HAMA-PBA), it provides injectability, flexibility, and efficient EGCG loading, along with outstanding mechanical properties and regulated release, effectively targeting inflammatory conditions [70]. A pH-sensitive hydrogel made from hyaluronic acid and collagen featuring “Double H-bonds” was developed to regenerate the extracellular matrix in diabetic wounds. The hydrogel self-forms in neutral and alkaline settings but breaks down in acidic wound conditions, releasing metformin. In vitro, it promotes fibroblast adhesion and infiltration while inhibiting macrophage proliferation, with metformin causing a transition in macrophages from M1 to M2, thereby enhancing fibroblast migration and collagen production. In vivo, it effectively reorganizes the extracellular matrix in diabetic wounds, accelerating the healing process [71]. A pH-sensitive metal-organic framework (MOF) system, MOF@HA@PCA, was developed for osteoarthritis (OA) therapy, discharging PCA to alleviate synovial inflammation in interleukin (IL)-1β-stimulated chondrocytes and OA joints, while lowering inflammatory markers and boosting the expression of cartilage-specific markers [72].

A nanosuspension of dexamethasone and hyaluronic acid was created for inhalation to treat acute lung inflammation while reducing systemic exposure. The aerosolized formulation demonstrated stability, efficient redispersion, and a core-shell nanoparticle structure (~200 nm) favorable for macrophage uptake. This framework enhances stability, provides muco-inert properties, and promotes effective deep-lung deposition. The formulation shows potential for direct nebulization in ventilators as a primary or additional therapy for lung inflammation [73]. In a rat model for gouty arthritis, a higher dose of BHA (50 μg) showed considerable anti-inflammatory effects by reducing joint swelling and lowering blood levels of IL-1β, IL-8, IFN-γ, and MCP-1 by 5.56%, 6.55%, 15.58%, and 33.18%, respectively. In a hyperuricemic mouse model, a lower dose of BHA (10 μg) effectively exhibited antioxidative effects by significantly lowering ROS levels in serum and liver by 14.87% and 8.04%, respectively, and enhancing liver superoxide dismutase (SOD) by 12.77%. Additionally, administering intraperitoneal BHA reduced uric acid production by lowering hepatic XO activity by 19.78% and decreasing serum uric acid levels by 30.41% in animals with hyperuricemia [74]. Derivatives of hyaluronic acid (o-HA) in the form of oligosaccharides were created to examine their effects on the progression of OA. In a chondrocyte model characterized by inflammation with LPS-stimulated ATDC5 cells, o-HA derivatives (≤100 μg/mL) demonstrated no cytotoxicity or pro-inflammatory properties. They reduced inflammation, apoptosis, autophagy, and proliferation inhibition caused by LPS, similar to HMW-HA. The Western blot analysis confirmed their role in regulating ECM-related proteins (matrix metallopeptidase 13 (MMP13), COL2A1, and Aggrecan). The results suggest that o-HA derivatives could offer a potential oligosaccharide-based therapy for OA by reducing inflammation, preserving cell viability, and preventing ECM degradation [75]. WSCPs/HA formulations notably improved wound closure rates, reaching complete closure in 18 h (WSCP1/HA) and 24 h (WSCP2/HA), while affecting the gene expression of MMPs, Ttransforming growth factor beta (TGF-β), and cyclooxygenase-2 (COX-2). CM derived from polarized cells enhanced healing with WSCP2/HA even more [76]. Type II diabetes mellitus (T2DM) is an inflammatory condition associated with inflammation of adipose tissue caused by obesity, resulting in insulin resistance. A new nanocomposite of CD44-targeted hyaluronic acid-functionalized graphene oxide quantum dots (GOQD-HA) was created for the purpose of metformin delivery. GOQD-HA-Met demonstrated lower levels of proinflammatory cytokines and a greater antioxidant capacity compared to free metformin in studies [77]. Subterranean mammals have high-molecular-weight hyaluronic acid, in contrast to their land-dwelling relatives. This accumulation arises from gene regulation and particular genetic alterations, improving skin elasticity and shielding against oxidative stress in low-oxygen subterranean settings, aiding their adaptation [78]. A microparticle made of hyaluronic acid, demonstrating enhanced lubrication, drug-delivery potential, antioxidant, and anti-inflammatory properties, was developed for the intra-articular treatment of temporomandibular joint osteoarthritis (TMJOA). These self-organizing microparticles, formed via hydrophobic interactions and boronate ester bonds, provide effective lubrication, radical neutralization, and antibacterial functions. In vitro studies confirmed their protective effects on chondrocytes exposed to oxidative stress, while in vivo experiments demonstrated their ability to reduce inflammation, prevent cartilage degradation, and promote matrix regeneration, making them a promising drug delivery approach for TMJOA treatment [79].

A HA hydrogel that penetrates cartilage was developed to enhance cartilage biomechanics and prevent deterioration after injury. The hydrogel improved the compressive modulus by 46.5% and lowered permeability in collagenase-treated samples. In a culture model of inflammation, hydrogel treatment preserved mechanical properties, retained matrix components, and reduced chondrocyte catabolic activity. The results suggest that HA hydrogels may enhance damaged cartilage, reducing inflammation and degradation, thus offering a promising approach for preventing osteoarthritis [80]. Hyaluronic acid and peptide-modified gold nanocages (HA-AuNCs/T/P) containing TPCA-1 were designed to enhance anti-inflammatory effects. The nanocages improved the cellular uptake of TPCA-1 compared to the unencapsulated drug, leading to more effective suppression of tumor necrosis factor (TNF)-α and IL-6. HA-AuNCs/T/P additionally reduced the production of reactive oxygen species in inflammatory cells [81]. Hyaluronic acid-linked, redox-sensitive polyamino acid nanogels (HA-NG) were designed for the precise delivery of TAC to inflamed joints in RA. The nanogels released TAC in response to increased intracellular glutathione levels in activated macrophages, thereby enhancing therapeutic efficacy and minimizing toxicity. In vitro and in vivo studies demonstrated that HA-NG/TAC significantly reduced inflammation, paw swelling, and bone erosion in murine models of rheumatoid arthritis [82]. Following exposure to noise, Toll-like receptor 4 (TLR4) and proinflammatory cytokines in the cochlea showed a significant rise from days three to seven after exposure. In the meantime, levels of HYAL2 and HYAL3 initially decreased but then rose above pre-exposure levels on day three, returning to baseline levels by day seven. Levels of HA, HAS2, and HYAL1 stayed consistent after exposure. In the LMW-HA group, alterations in hearing thresholds and the expression of TLR4, TNF-α, and IL-1β were more significant than in the control and HMW-HA groups. In the LMW-HA and control groups, proinflammatory cytokines increased from day three to seven, while they diminished in the HMW-HA groups [83]. Cajaninstilbene acid and rat urinary exosomes (CUEHD), an artificial mucus made from dopamine-modified hyaluronic acid, cajaninstilbene acid, and rat urine exosomes, has been created to address endometrial dysfunction in a rat model. Its robust elastic and adhesive characteristics boost retention, enhancing therapeutic efficacy and biosafety. CUEHD therapy enhances endometrial thickness, improving receptivity and fertility, while preserving estrogen balance, decreasing inflammation, and fostering endometrial regeneration via endoplasmic reticulum (ER)- nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3)-IL1β and Wnt-β catenin signaling pathways. The potential of exosomes derived from human urine and ADSCs is emphasized (Fig. 7) [84].

Fig. 7. CUEHD-Mediated Endometrial Regeneration via Anti-Fibrotic and Anti-Inflammatory Pathways.

a In rats with reduced endometrial thickness, injectable CUEHD mucus disperses within the uterine cavity, preventing intrauterine adhesions and supporting endometrial regeneration. b CUEHD promotes the production of abundant Ru-EXOs, which regulate TGFβ signaling by suppressing TGFβ1 and TGFβ2 while upregulating TGFβ3. Inhibition of TGFβ receptors 1 and 2 subsequently activates β-catenin and blocks smad2/3 phosphorylation, thereby reducing fibrosis and enhancing regenerative pathways. Meanwhile, CSA stimulates ERα/β activity, which suppresses NLRP3-IL1β signaling and strengthens anti-inflammatory responses. The synergistic actions of Ru-EXOs and CSA within CUEHD collectively improve both the structural restoration and functional regeneration of endometrial tissue in rats. Reprinted with permission from Wiley [84]

The gut microbiota in Sub mice is deficient in vital microorganisms, such as Lactobacillus and Bifidobacterium, which are important for immune system development. From birth, they display a thicker colon mucin layer and, in early adulthood, a reduced colonic length, weakened colon integrity, increased gut permeability, diminished short chain fatty acids (SCFA) levels, and fewer regulatory T-cells compared to Dom animals. Adult Sub mice administered HA, celecoxib, or a combination of both exhibited enhancements: HA decreased gut permeability and increased colon length and social behaviors, whereas celecoxib boosted sociability and mental well-being [85]. A hyaluronic acid-based polymer (HAMPC) was created by grafting 2-methacryloyloxyethyl phosphorylcholine (MPC) to enhance lubrication for osteoarthritis treatment. The HAMPC showed significantly lower friction compared to HA, improved biocompatibility, and increased anabolic genes linked to cartilage, while also reducing catabolic and pain-related genes. High molecular weight HAMPC demonstrated greater effectiveness in regulating these genes [86].

A consistently wet environment is essential for wound healing, attainable with an in situ hydrogel that emulates the strength of skin tissue and has self-repairing properties. This research outlines the development of robust self-healing hydrogels based on hyaluronic acid using a dual-crosslinking method that integrates acylhydrazone bonds and photocrosslinking with modified sodium hyaluronate. These hydrogels provide quick gelation (in less than 1 minute), regulated swelling, and outstanding biocompatibility, demonstrating mechanical strength comparable to human skin (around 2.2 kPa) and more than 90% self-healing capability within 6 h. They improve every phase of wound healing, making them a great option for repairing full-thickness skin wounds (Fig. 8) [87].

Fig. 8.

Illustration comparing the AMDH hydrogel with the AMDH hydrogel following UV exposure. Reprinted with permission from Elsevier [87]

Myocardial infarction (MI) is a critical heart condition characterized by high rates of complications and mortality. Exo therapy is a viable choice for ischemic myocardial infarction because of its advantageous characteristics. Nonetheless, conventional Exo delivery is imprecise in directing to the lesion area. This research created an injectable OHA-PL hydrogel to entrap ADSC-Exos, improving their retention. The OHA-PL@Exo hydrogel is inserted into the ischemic heart muscle to diminish oxidative stress, manage inflammation, and ultimately enhance fibrosis, remodeling, angiogenesis, and cardiac function during recovery from myocardial infarction (Fig. 9) [88].

Fig. 9.

The OHA-PL@Exo hydrogel was delivered into the injured myocardium of a rat myocardial infarction model, where it alleviated oxidative stress, modulated macrophage polarization, reduced myocardial fibrosis, and enhanced angiogenesis, thereby supporting cardiac repair. Reprinted with permission from Elsevier [88]

The effects of a sulfasalazine-infused hyaluronic acid (SASP/HA) system were studied for its anti-inflammatory effects and its capacity to reduce cartilage damage in LPS-stimulated synoviocytes in a rat model of MIA-induced OA. The SASP/HA system provided SASP reliably for a period of up to 60 days. In vitro, SASP/HA inhibited pro-inflammatory cytokines such as MMP-3, COX-2, IL-6, and TNF-α in a dose-dependent fashion. In vivo, the administration of SASP/HA into the joint reduced the levels of MMP-3, COX-2, IL-6, and TNF-α, alleviating the progression of MIA-induced osteoarthritis and cartilage damage, as observed through X-ray, micro-CT, and histological evaluations [89]. A strategy for gene therapy was developed to regulate cartilage inflammation and degeneration in OA by merging interference oligonucleotides with Au nanorods to form SNAs for enhanced stability and cellular uptake. The SNAs were delivered through DNA-grafted hyaluronic acid (DNAHA), improving injectability and biostability. The DNAHA-SNAs system (HA-SNAs) enabled the reversible liberation of SNAs stimulated by NIR light through photothermal DNA dehybridization. In vitro and in vivo research demonstrated that HA-SNAs effectively influenced cartilage catabolic and anabolic factors, protecting chondrocytes and slowing the progression of osteoarthritis (Fig. 10) [90].

Fig. 10. Photothermal-Triggered HA-SNAs System for IL-1β Gene Silencing.

a A multifunctional HA-SNAs platform is engineered via DNA hybridization, which disassembles under photothermal stimulation to release SNAs. b DNAHA is chemically modified and base-paired with SNAs designed to target IL-1β. c After intra-articular injection of the HA-SNAs system, exposure to NIR light induces controlled SNA release, enhancing cellular uptake and enabling mRNA interference to suppress IL-1β expression. c(i) depicts cellular uptake; c(ii) shows SNAs binding to target mRNA; c(iii) illustrates inhibition of translation; c(iv) represents transcription from DNA to mRNA; and c(v) demonstrates translation of mRNA into IL-1β protein. Reprinted with permission from Wiley [90]

The research examined a CMCS/OHA hydrogel loaded with stem cell Exo for the treatment of chronic inflammatory wounds. This hydrogel facilitated prolonged Exo release for 6 days, improving macrophage activities in vitro. In vivo, it greatly enhanced wound healing, re-epithelialization, collagen synthesis, and decreased the release of inflammatory factors, surpassing control groups and promoting quicker recovery from chronic wounds [88]. An intervention method with dual functions and locations is introduced, utilizing hyaluronic acid-nanocoated Clostridium butyricum to provide anti-inflammatory and tissue-repair benefits in both the gastrointestinal system and external organs. The nanocoated bacteria reduce intestinal mucosal inflammation and restore gut barrier integrity by leveraging the immunosuppressive properties of hyaluronic acid alongside the butyrate-producing abilities of Clostridium butyricum. Additionally, they reduce interstitial inflammation and tissue damage in organs outside the intestine by influencing microbial metabolites and decreasing microbial translocation. In mouse models of acute kidney injury and chronic kidney disease, the oral delivery of nanocoated bacteria effectively restores renal function and diminishes renal fibrosis (Fig. 11) [91].

Fig. 11.

Orally administered Spore@CH primarily localizes in the affected intestine, where it mitigates intestinal inflammation and restores barrier integrity. In addition, it alleviates interstitial inflammation and tissue injury in extraintestinal organs by modulating microbial metabolites and reducing microbial translocation. This oral delivery strategy provides a novel means of addressing AKI and CKD by promoting renal function recovery and reducing renal fibrosis, respectively. Reprinted with permission from Wiley [91]

A dual-bioresponsive strategy employing Rhein (RH) was developed to improve colonic mucosal healing and manage inflammation for the effective treatment of ulcerative colitis (UC). This approach combines dual-targeting of intestinal epithelial cells and macrophages through an oral nano delivery system. Lactoferrin (LF) NPs were altered with two carbohydrates, CP and HA, to encapsulate RH (CP/HA/RH-NPs). The CP layer stabilizes the nanoparticles, protecting them from the harmful gastrointestinal environment, and aids in the release of HA/RH-nanoparticles at the site of colonic lesions. Studies on cellular uptake revealed that the nanoparticles effectively targeted and enhanced uptake through LF and HA ligands. In vivo experiments demonstrated that CP/HA/RH-NPs significantly reduced inflammation by blocking the TLR4/MyD88/nuclear factor kappa B (NF-κB) signaling pathway and accelerated colonic healing. This study is the initial examination of LF as a specific nanomaterial for the treatment of ulcerative colitis (Fig. 12) [92].

Fig. 12.

When administered orally in mouse models, CP/HA/RH-NPs travel through the gastrointestinal tract, where the CP shell shields the particles in the stomach and small intestine before releasing HA/RH-NPs into the colonic lumen upon degradation. These nanoparticles aid in repairing intestinal injury by selectively targeting colonic epithelial cells and regulating the expression of ZO-1 and Claudin-1. Furthermore, macrophage-targeted delivery enhances the anti-inflammatory activity of RH by modulating the TLR4/MyD88/NF-κB signaling pathway, thereby improving in vivo therapeutic outcomes for ulcerative colitis. Reprinted with permission from Elsevier [92]

The treatment of OA is challenging due to its complex etiology. Intra-articular injections of medications, such as glucocorticoids and HA, have drawbacks like the risk of infection, discomfort, and swelling. Hydrogel-based therapeutic approaches have gained significant attention owing to their effectiveness in treatment. This study creates a supramolecular nanofiber hydrogel utilizing DexP as a carrier for transporting lentivirus that encodes HAS2 (HAS2@DexP-Gel). As hydrogel decomposition occurs, the HAS2 lentivirus and DexP molecules are gradually released. Intra-articular delivery of HAS2@DexP-Gel boosts natural hyaluronic acid production and diminishes synovial inflammation. Additionally, HAS2@DexP-Gel reduces subchondral bone loss in osteoarthritis mice induced by anterior cruciate ligament transection, alleviates cartilage degradation, and slows the progression of osteoarthritis. The hydrogel demonstrated excellent biocompatibility in both in vitro and in vivo environments. The therapeutic actions of HAS2@DexP-Gel were examined through single-cell RNA sequencing, showing its ability to improve the synovial tissue microenvironment by modifying the ratios of synovial cell subpopulations and managing interactions between synovial fibroblasts and macrophages. The HAS2@DexP-Gel nanofiber hydrogel greatly enhances the endogenous synthesis of HA and diminishes synovial inflammation (Fig. 13) [93].

Fig. 13. HAS2@DexP-Gel Alleviates Osteoarthritis via Synovial and Cartilage Protection.

A In osteoarthritic joints, articular cartilage undergoes degradation, subchondral bone resorption is elevated, and synovitis develops, characterized by thickened synovial membranes, infiltration of inflammatory cells, and pannus formation. B Following administration, HAS2@DexP-Gel degrades to release HAS2 lentivirus and DexP. The lentivirus transduces fibroblast-like synoviocytes (FLS), enhancing endogenous hyaluronic acid production, while DexP suppresses M1 macrophage activity by modulating the PI3K/AKT/mTOR/HIF-1α pathway. Together, these actions alleviate synovitis and slow cartilage degeneration. Reprinted with permission from Wiley [93]

In a mouse model of experimental autoimmune encephalomyelitis (EAE), brain glycosaminoglycans (GAGs) were analyzed, showing that neuroinflammation caused a decrease in CS and an increase in HA at the peak of the illness, with changes that were partially reversible during recovery. Changes in GAG metabolism, marked by the increased expression of genes linked to HA and decorin synthesis as well as GAG breakdown, were observed, suggesting that early GAG modifications might be aimed at reducing EAE/MS progression [94]. A formulation of Visudyne (VP) combined with ProVisc® HA gel was developed to reduce corneal fibrosis, neovascularization, and inflammation after injury. The hybrid gel significantly improved VP’s retention on the eye surface, leading to reduced corneal opacity and improved healing, while maintaining epithelial repair in a rat model, suggesting potential for scar-free corneal healing [95]. A responsive, anti-inflammatory hydrogel (HA-ADH/OHES@XT) was created through the crosslinking of oxidized hydroxyethyl starch and hyaluronic acid, enabling the prolonged release of xanthatin (XT). The hydrogel demonstrated suitable properties for wound healing, including water retention, self-repair, biodegradability, and biocompatibility. In vivo, it promoted tissue regeneration, reduced inflammation, and enhanced collagen deposition, achieving approximately 89.1% wound healing by day 20, highlighting its promise as an effective wound dressing [96]. An innovative dissolving microneedle patch was created for the healing of oral ulcers, designed with a core-shell structure that includes basic fibroblast growth factor within a gelatin shell, a hyaluronic acid core containing dexamethasone, and zeolite imidazoline framework-8 to provide antimicrobial effects. The patch enabled sustained bFGF release to promote healing, while HA and DXMS reduced inflammation. The residual MN support acted as a framework, aiding the discharge of ZIF-8 for antibacterial effectiveness. This versatile patch demonstrated exceptional anti-inflammatory, antibacterial, and healing-enhancing characteristics, suggesting its potential use for treating oral ulcers [97].

Beyond the approaches already explored, future investigations into HA in inflammation regulation should examine its role in fine-tuning immune cell signaling pathways, especially in balancing pro- and anti-inflammatory macrophage phenotypes and T-cell subsets, as well as its potential to modulate the gut–immune axis through microbiota interactions. Further research could also explore synergistic combinations of HA with bioactive molecules (peptides, exosomes, small-molecule drugs, or gene therapies) to enhance targeted delivery and long-term therapeutic effects, while minimizing systemic side effects. Additionally, understanding the influence of HA molecular weight, structural modifications, and degradation products on inflammatory cascades in different tissues and disease contexts (such as neuroinflammation, metabolic disorders, and cardiovascular inflammation) will be crucial. Expanding HA’s applications in personalized and responsive delivery systems that adapt to the dynamic inflammatory microenvironment could also unlock new opportunities for precision medicine in chronic inflammatory diseases.

Anti-bacterial activity

The focus of a study was on controlling drug release from titanium nanotube (Ti-NT) by employing polydopamine and hyaluronic acid films, aiming to attain antibacterial effectiveness and enhance osteogenesis. Vancomycin was integrated into Ti-NT, whereas dopamine and hyaluronic acid were attached to the exterior. The modified Ti-NT exhibited increased drug loading, extended release for 7 days, enhanced antibacterial properties, and promoted osteogenic differentiation of rat bone marrow stem cells [98]. Hydrogel coatings based on hyaluronic acid were utilized on Ti6Al4V biomaterial through the use of 1,4-butanediol diglycidyl ether and divinyl sulfone as crosslinking agents. These coatings exhibited remarkable biocompatibility, enhanced cell growth, differentiation, and mineralization, facilitated prolonged drug release, and showed strong antibacterial properties against S. aureus and E. coli through various mechanisms [99]. Antibacterial coatings made of polysaccharides were developed on altered titanium surfaces to serve as storage for antibacterial agents. Hyaluronic acid and chitosan polyelectrolyte multilayers were created on Ti-6Al-4V alloys, with an analysis of surface properties and assessment of antibacterial activity against Staphylococcus aureus conducted [100]. A composite hydrogel system incorporating dexamethasone (DE), HA, and chitosan (CT) demonstrated extended drug release and compatibility with biological systems. It demonstrated antibacterial efficacy against MRSA and E. coli, while decreasing inflammatory markers, emphasizing its potential for treating peri-implantitis [101]. An injectable hydrogel (HA@Cur@Ag) responsive to ROS was created for healing diabetic wounds, incorporating curcumin liposomes and silver nanoparticles, which improve healing by scavenging ROS, providing antibacterial benefits, and exhibiting anti-inflammatory effects, suppressing TNF/NF-κB (Fig. 14) [102].

Fig. 14. Stepwise Synthesis of HA@Cur@Ag Hydrogel Incorporating Curcumin and AgNPs.

Development and evaluation of HA@Cur@Ag hydrogel for diabetic wound therapy: A Synthesis of HB-PBHE. B Preparation of SH-HA. C Fabrication of curcumin liposomes using microfluidic blending. D Formation of the HA@Cur@Ag hydrogel by cross-linking SH-HA with HB-PBHE in the presence of curcumin liposomes and AgNPs. Reprinted with permission from Wiley [102]

A bioadhesive was developed using coacervates made from recombinant MAP and dopamine-altered HA. Dopamine improved the rheological properties, making the coacervates more adaptable, injectable, and ideal for wound sealing. The coacervates displayed inherent antibacterial characteristics against Staphylococcus aureus and Escherichia coli, with the antibacterial effect linked to catechol presence. Additionally, the addition of the bioactive peptide thymosin boosted fibroblast migration, thereby improving the bioactivity of the coacervates [103]. A hydrogel dressing with multifunctional properties (HAMA-TPP-DMA) was created through a redox-initiated cross-linking method that included methacrylated hyaluronic acid, porphyrin photosensitizer (TPP), and dopamine methacrylamide. This hydrogel exhibited significant photodynamic antibacterial effectiveness, biodegradability, biocompatibility, and enhanced adhesiveness, aiding in wound healing. Both in vitro and in vivo research demonstrated its effectiveness in fighting germs and enhancing wound healing, achieving a closure rate exceeding 98% after 15 days in mice [104]. A hydrogel dressing that mimics multifunctional ECM was developed for open wound treatment, incorporating TA and EPL into a Gel/HA framework. The hydrogel exhibited hemostatic, antimicrobial, and reactive oxygen species-eliminating properties, as well as stable rheological characteristics, biodegradability, and advantageous biocompatibility. Both in vitro and in vivo evaluations revealed its effectiveness in boosting extracellular matrix generation and accelerating wound healing [105]. A hydrogel dressing that mimics multifunctional ECM was developed for open wound treatment, incorporating TA and EPL into a Gel/HA framework. The hydrogel exhibited hemostatic, antimicrobial, and reactive oxygen species-eliminating properties, as well as stable rheological characteristics, biodegradability, and advantageous biocompatibility. Both in vitro and in vivo evaluations revealed its effectiveness in boosting extracellular matrix generation and accelerating wound healing [106]. Hydrogels that are injectable and responsive to acidic conditions, ROS, and high glucose levels were developed to deliver TA for addressing chronic diabetic wounds. The hydrogel, created through the crosslinking of modified HA, releases TA in response to the diabetic microenvironment, promoting antibacterial, anti-inflammatory, and antioxidative effects. In vivo studies on diabetic mice demonstrated that the hydrogel enhanced angiogenesis and extracellular matrix formation, leading to full wound closure, thereby offering a promising method for treating chronic diabetic wounds [107]. Antibacterial polymeric coatings utilizing PVP, HA, and CHI were created for Ti6Al4V implants, incorporating catechol as a bioadhesive. Their adhesive qualities, stability, compatibility with cells, and antibacterial characteristics were assessed, validating their efficacy in preventing infections [108]. A hydrogel made of hyaluronic acid (HMn) with antibacterial and antioxidant characteristics was created by incorporating MnO2 nanosheets into a crosslinked methacrylated hyaluronic acid (HAMA) framework utilizing 4ARM-PEG5000-SH. The sulfhydryl groups of 4ARM-PEG5000-SH attach to MnO2 nanosheets, embedding them in the hydrogel, and facilitating gelation via a thiol-ene click reaction. Under NIR light, HMn exhibits a bactericidal effectiveness of 95.24% against Staphylococcus aureus and close to 100% against Escherichia coli, illustrating significant wound healing capability with low toxicity [109]. Handling infected wounds in diabetic patients poses considerable difficulties in healthcare environments. Lately, multifunctional hydrogels have attracted interest for their role in wound healing. This research created a drug-free, non-crosslinked hydrogel hybrid of chitosan and hyaluronic acid, utilizing their synergistic advantages to address MRSA-infected diabetic wounds. The hydrogel demonstrated significant antibacterial properties, boosted fibroblast growth and movement, provided excellent ROS neutralization, and safeguarded cells, ultimately enhancing wound healing by eliminating infections and facilitating tissue regeneration (Fig. 15) [110].

Fig. 15.

Diagram showing the preparation of CS/HA hybrid hydrogels and their use in treating infected diabetic wounds. reproduced with permission from Elsevier [110]

An injectable antibacterial hydrogel that merges HA and CHX was created for the treatment of CIED infections. HA underwent pre-crosslinking with BDDE, was ground into microgel (CHA), and CHX was electrostatically linked into CHA, resulting in hybrid crosslinked hydrogels (CHA/CHX). These hydrogels exhibited shear-thinning and self-recovery characteristics, allowing for easy injection into the CIED pocket and ensuring an ideal fit with the pocket’s shapes without requiring additional space, indicating a progress compared to previous methods. Antibacterial tests conducted both in vitro and in vivo showed that the CHA/CHX hydrogels exhibited excellent biocompatibility and strong antibacterial effectiveness [111]. Hydrogels with dual cross-linking made from OHA and N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) methacrylate (HTCCMA) were developed for the purpose of cartilage regeneration. These hydrogels exhibited outstanding rheological properties, self-repair capabilities, prolonged tissue adhesion, and remarkable lubrication with low friction coefficients (0.065 and 0.078). The hydrogels showed antimicrobial effects, promoted cell growth, and proved to be biocompatible and biodegradable (Fig. 16) [112].

Fig. 16. Dual-Cross-Linking Strategy of OHA/HTCCMA Hydrogel in Cartilage Repair.

Diagram depicting A OHA preparation, B HTCCMA production, and C dual-cross-linked OHA/HTCCMA hydrogel formation for cartilage repair. Reproduced with approval from Elsevier [112]

Periodontitis is marked by the gradual deterioration of periodontal tissues caused by inflammation induced by bacteria. This research presents an injectable hydrogel, Shed-Cu-HA, aimed at treating periodontal pockets by embedding Cu²⁺ and Shed-exo into a HA framework. The hydrogel’s regulated release of Cu²⁺ and Shed-exo enhances the survival and proliferation of human periodontal ligament stem cells. It demonstrates considerable antibacterial properties against Aggregatibacter actinomycetemcomitans and decreases macrophage-driven inflammation via the IL-6/JAK2/STAT3 pathway. In a mouse model, Shed-Cu-HA therapy reduced inflammation and bacterial infection while promoting periodontal tissue healing. Its ability to address periodontitis is encouraging (Fig. 17) [113].

Fig. 17.

Diagram showing the preparation of Shed-Cu-HA hydrogel and its combined antibacterial, anti-inflammatory, and osteogenic roles in periodontal bone repair. Reproduced with consent from ACS [113]

HA-AZI/Qe-M possessed beneficial physical and chemical properties. In vitro antibacterial tests demonstrated its effectiveness in diminishing MRSA growth, breaking down and eliminating MRSA biofilms, and tackling intracellular bacterial infections. Studies on cellular uptake using RAW264.7 cells, along with in vivo imaging, showed that HA-AZI/Qe-M improved cellular internalization, targeted infection sites, and extended therapeutic effectiveness. In vivo antibacterial assays showed that HA-AZI/Qe-M reduced thigh muscle infections in mice and lowered the levels of inflammatory markers [114]. A dissolving MN device made of MoS₂ and chitosan was developed for painless transdermal drug delivery with antibacterial properties. The HA-based MNs demonstrated sufficient mechanical strength, biocompatibility, and minimal irritation. Laboratory studies confirmed their antibacterial efficacy against E. coli and S. aureus, while live animal wound healing experiments revealed their healing potential for wounds associated with infections [115]. Three biodegradable wound dressings composed of COL and HA, infused with AgNPs, GENT, or a combination of both, were effectively produced through freeze-drying. FTIR-ATR validated chemical interactions, and swelling and degradation tests indicated quick biodegradability within three days. The dressings showed antibacterial effects against different types of bacteria and yeast. Cytotoxicity assessments demonstrated favorable biocompatibility, with the exception of the COL/HA/AgNPs/GENT membrane. COL/HA/AgNPs and COL/HA/GENT demonstrated greater effectiveness in wound healing [116]. HA-based hydrogels demonstrate promise as wound dressings, but their effectiveness is restricted for diabetic wounds because of ongoing inflammation and infection. This research presents a dynamically crosslinked HA hydrogel (Gel-HAB) that incorporates allomelanin (AMNP) and BNN6 nanoparticles for healing diabetic wounds. The acylhydrazone connection offers injectability and self-repair features. Gel-HAB effectively eliminates ROS and emits NO when exposed to NIR laser light, providing antibacterial properties. It efficiently diminishes oxidative stress, manages infections, promotes vascular regeneration, and speeds up healing of diabetic wounds (Fig. 18) [117].

Fig. 18.

Diagram showing the preparation and use of Gel-HAB hydrogel dressing with photothermal antibacterial effects for diabetic wound healing. Reproduced with approval from Elsevier [117]

Osteomyelitis, a complex orthopedic condition frequently associated with medical implants, poses significant treatment challenges due to bacterial biofilm formation and the limited effectiveness of prolonged antibiotic delivery. To mitigate this issue, a pH-responsive hydrogel coating, consisting of nano-TiO₂-modified chitosan/gelatin/aldehyde hyaluronic acid (CS/Gel/AHA) and zeolitic imidazolate framework (ZIF), was developed via dip-coating [118]. This coating offers robust mechanical stability while releasing Ca²⁺ to disrupt bacterial Bap protein and inhibit biofilm formation, in conjunction with vancomycin to eradicate free bacteria. This approach demonstrates considerable antibacterial efficacy both in vitro and in a rat subcutaneous implant model, underscoring its potential for addressing implant-related infections. Bacterial prostatitis, a common male genitourinary disorder exacerbated by increasing fluoroquinolone resistance, was addressed using a novel delivery system comprising a luteolin–copper complex conjugated with hyaluronic acid [119]. This system enhanced luteolin’s solubility, stability, and bioavailability, facilitating controlled pH-dependent release, and exhibited significant antibacterial efficacy and favorable hemocompatibility in vitro, thereby laying the groundwork for luteolin’s clinical application. A dual-function therapy utilizing hyaluronic acid-nanocoated Clostridium butyricum was developed to concurrently address gut inflammation and extraintestinal diseases [91]. This strategy merges the immunosuppressive properties of hyaluronic acid with the butyrate-producing capabilities of the bacteria. It not only restored intestinal barrier integrity and diminished mucosal inflammation but also ameliorated pathological damage in extraintestinal organs, including the kidneys, by modulating microbial metabolites and minimizing translocation. This approach demonstrated therapeutic efficacy in murine models of acute kidney injury and chronic kidney disease, indicating its potential as a next-generation living therapeutic for systemic inflammatory disorders.

Antioxidant activity

An innovative viscosupplementation agent utilizing HA was developed by combining HA, (2-hydroxypropyl)-β-CD, and VE to enhance intra-articular treatments. This ternary system, lacking formal chemical bonds, demonstrated improved viscoelasticity and lubrication properties, antioxidant effectiveness, along with superior hydrophobic drug loading and release abilities. Rheological studies showed synergistic effects and improved thermal stability linked to VE. Biocompatibility studies conducted on L929 cells confirmed the safety of HCV, showing enhanced expression of the anti-inflammatory cytokine interleukin-10 [120]. Liver fibrosis is a significant and irreversible condition mainly triggered by HSCs, which transition from an inactive to an activated form due to ongoing liver injury. This activation leads to increased collagen buildup, elevated CD44 expression on HSC surfaces, and intensified oxidative stress, thereby worsening fibrosis. A therapy method was developed that combines CD44-targeting of activated hepatic stellate cells with an antioxidative approach. HABNs)were created using bilirubin—an inherent antioxidant and anti-inflammatory bile acid—and hyaluronic acid, a glycosaminoglycan biopolymer that targets CD44. Intravenous administration of HABNs effectively concentrated in the liver, specifically targeting activated HSCs, in fibrotic mice that exhibited NASH induced by a choline-deficient l-amino acid-defined high-fat diet (CD-HFD). HABNs inhibited HSC activation and growth, while reducing collagen production. In a mouse model of NASH fibrosis induced by a CD-HFD, HABNs administered intravenously showed notable antifibrotic effects (Fig. 19) [121].

Fig. 19. Synthesis, Characterization, and Therapeutic Mechanism of HABNs in Liver Fibrosis.

CD44-targeted antioxidant HABNs for liver fibrosis therapy: a Illustration of the self-assembly of HABNs formed from hyaluronic acid and bilirubin. b TEM image of HABNs with a 200 nm scale bar. c Schematic showing the therapeutic mechanism, where CD44-targeting HABNs alleviate oxidative stress in activated HSCs, thereby suppressing their activity and collagen synthesis, ultimately slowing the progression of liver fibrosis. Reproduced with authorization from ACS [121]

The overproduction of ROS in IBD results in disrupted signaling, inflammatory reactions, and DNA damage, accelerating disease progression. Consequently, ROS scavenging may serve as a possible therapy for IBD. A diselenide-bridged hyaluronic acid nanogel (SeNG) was created as an oral formulation to address colitis, leveraging the CD44-binding characteristics of hyaluronic acid and diselenide substances for reactive oxygen species scavenging. In a mouse model, SeNG exhibited notable anti-inflammatory properties by lowering ROS levels and stimulating the Nrf2/HO-1 signaling pathway (Fig. 20) [122].

Fig. 20. Synthesis, Targeting, and Antioxidant Mechanism of SeNG in Colitis.

a–c SeNG demonstrates protective effects in a colitis model through intrinsic ROS-scavenging capacity and CD44-mediated targeting of inflamed tissues. It is synthesized directly via an emulsion-based method. The strong HA–CD44 interaction ensures precise accumulation at disease sites. c Mechanistically, SeNG exerts potent antioxidant activity by both directly neutralizing ROS and modulating the Nrf2 signaling pathway. This leads to enhanced expression of anti-ROS proteins (HO-1, SOD, CAT, GSH, GST) and concurrent suppression of iNOS and pro-inflammatory cytokines such as TNF-α and IL-6. Published again with permission from ACS [122]

Skin harm caused by different stressors and aging was successfully treated with a supramolecular formulation of HA-ECT. Theoretical and empirical research demonstrated that the combination of hyaluronic acid and ectoin produced a stable, permeable compound that improves skin absorption. HA-ECT demonstrated 3.39 times greater permeability compared to ectoin alone, enhancing the growth of keratinocytes and fibroblasts, elevating type I collagen levels, decreasing inflammatory markers, and boosting hydration. Furthermore, it reduced reactive oxygen species and decreased matrix metalloproteinase-1 expression, contributing to skin rejuvenation [123]. A composite hydrogel composed of hyaluronic acid, which includes a dopamine-substituted antimicrobial peptide (DAP) and iron (III) ions, was created to improve healing in wounds infected by bacteria. This hydrogel possesses antibacterial, antioxidant, and photothermal attributes, aiding in bacteria removal and wound healing. DAP functions as an antibacterial agent and a ROS scavenger, enhancing the integrity of the hydrogel. Research has validated its efficacy in antibacterial properties and tissue repair [124]. A bioink was created by combining hyaluronic acid (HAGA) functionalized with gallic acid and HAMA to enhance the print quality in 3D bioprinting. HAGA improves viscosity and printability, whereas HAMA facilitates stable hydrogel formation, showing enhanced viscoelasticity and antioxidant capabilities [125].

Beyond the current strategies, future exploration of HA in antioxidant activity could focus on tailoring its molecular weight and chemical modifications to optimize ROS scavenging efficiency, as different HA fragments may differentially influence redox signaling and cellular responses. Combining HA with natural polyphenols, metal chelators, or enzymatic antioxidants could yield multifunctional systems capable of targeting diverse oxidative pathways in chronic diseases such as neurodegeneration, cardiovascular disorders, and metabolic syndromes. Additionally, the design of stimuli-responsive HA-based carriers that release antioxidants in response to oxidative microenvironments could improve site-specific therapeutic effects while minimizing off-target actions. Investigating HA’s role in regulating mitochondrial oxidative stress and its interplay with intracellular antioxidant defense systems, as well as expanding its applications in cosmetic and regenerative medicine to prevent ROS-driven tissue aging, may also provide valuable insights. Furthermore, integrating HA-antioxidant platforms with advanced biomaterials such as microneedles, nanofibers, and organ-on-chip models could enhance their translational potential for precise, long-term, and patient-tailored antioxidant therapies.

Diabetes mellitus

Sponge scaffolds based on hyaluronic acid (H1P4D2@DFO) were developed by combining pig acellular dermal matrix, hyaluronic acid, and polydopamine nanoparticles loaded with deferoxamine mesylate (PDA@DFO) to enhance vascularization and promote healing of diabetic wounds. The scaffold, marked by enhanced cell attachment, porosity, and water uptake, utilized NIR photothermal therapy and a sustained release of deferoxamine to improve wound vascularization. The construction of the 3D scaffold promoted angiogenesis and accelerated healing, showing potential for applications in chronic wound treatment [126]. The healing of wounds in diabetics is an increasing global healthcare concern because of bacterial infections and inflammation. Controlling these injuries may be improved by stopping bacteria and encouraging macrophage polarization. A new hydrogel (GH/LA) was created employing glycyl methacrylate gelatin, oxidized hyaluronic acid, and lauric acid. This hydrogel demonstrated remarkable compressive strength and adhesion, and in diabetic wound models, it displayed antibacterial, anti-inflammatory, and healing properties by enhancing M2 macrophage polarization via the GPR40/NF-κB pathway (Fig. 21) [127]. In diabetic wounds, inadequate phenotypic switching of macrophages leads to ongoing non-healing. Exosomes derived from M2 macrophages (M2Exo) can shift M1 macrophages toward the M2 phenotype and accelerate healing. This project entailed the conjugation of M2Exo with oxidized hyaluronic acid, which was then integrated with PEGylated silk fibroin to develop a self-healing Exo-gel. The Exo-gel showed exceptional water retention and self-repair properties, promoting fibroblast growth and movement in vitro. In a diabetic rat model, Exo-gel therapy resulted in 75% wound closure in 7 days, complete regeneration of the epithelium, and improved angiogenesis and collagen accumulation, making it a promising treatment for chronic diabetic wounds [128]. The treatment of diabetic wounds is worsened by bacterial infections that increase inflammation. Polysaccharide hydrogels with inherent antibacterial properties can reduce reliance on medications for managing infections. Traditional hydrogels rely on bacteria entering their porous structure, which may obstruct the healing process. Improving antibacterial effectiveness requires swift bacterial capture and removal. HAQ, a versatile hydrogel dressing composed of modified hyaluronic acid, phenylboronic acid, and chitosan, demonstrates considerable antibacterial effectiveness against antibiotic-resistant bacteria. It shows potential for effectively managing bacterial infections in wounds caused by diabetes [129].

Fig. 21. In Situ Formed GH/LA Hydrogel Promotes Hemostasis, Antibacterial Action, and Tissue Repair.

A–B Gel-Gym and HA-CHO, combined with LA, were injected into the wound site and exposed to UV light, rapidly forming an in situ hydrogel to cover the wound. The resulting GH/LA hydrogel reduces bleeding, suppresses bacterial proliferation, drives macrophage polarization toward the M2 phenotype, and enhances angiogenesis, thereby accelerating the healing of MRSA-infected wounds. CD68 and Arg-1 served as markers for macrophages. Published with consent from Elsevier [127]

Challenging treatment of refractory diabetic wounds arises from their high prevalence and oxidative stress that obstructs healing. A multifunctional hyaluronic acid hydrogel dressing (GHPM) was created, providing remarkable tissue adhesion, antimicrobial features, and antioxidant benefits. GHPM encourages wound closure, minimizes infection, improves collagen deposition, and, when paired with electrical stimulation, enhances angiogenesis and neurogenesis, supporting healing in diabetic wounds (Fig. 22) [130].

Fig. 22.

Illustration demonstrating how the GHPM hydrogel is formed and applied as a wound covering to treat infected skin injuries. Published again with consent from Elsevier [130]

Wounds in diabetics are prone to increased inflammation and recurrent bacterial infections because of weakened immune response, hindering the healing process. This study focused on altering HA with DA and merging it with COR to create a nanofiber wound dressing (COR/OHDA/GEL) via electrostatic spinning. The coating demonstrated outstanding thermal stability, water affinity, and air permeability. In vitro, it showed considerable antibacterial effects (S. aureus: 95.60%, E. coli: 71.17%), antioxidant effectiveness (>90%), and compatibility with biological systems. In vivo, it aided wound healing by enhancing tissue remodeling, collagen accumulation, and the restoration of granulation tissue. Western blot analysis revealed that the dressing reduced severe inflammation via the TLR4/NF-κB pathway, suggesting it as a possible method for treating chronic diabetic wounds [131]. Chronic diabetic wounds that fail to heal create a major healthcare challenge, primarily because of persistent inflammation and impaired angiogenesis. This study produced a bioactive scaffold inspired by mussels, made of collagen and hyaluronic acid, aimed at healing diabetic wounds. Different concentrations of collagen-hyaluronic acid scaffolds modified with polydopamine (CHS-PDA-0.5, CHS-PDA-1, CHS-PDA-2) were created and assessed for their physical properties, antioxidant advantages, inflammation modulation, and abilities for drug loading/release. The optimal scaffold, CHS-PDA-2@EGF, loaded with EGF, showed resistance to ROS, reduced inflammation, and promoted chronic wound healing in diabetic rats. The scaffold exhibited enhanced swelling, coagulation, and degradation properties, highlighting its potential as a cost-effective and efficient dressing for the treatment of diabetic wounds [132]. Diabetic wounds frequently result in disabilities and amputations of the lower limbs because current treatments are ineffective. This research investigated the therapeutic properties of TMP, a natural alkaloid derived from Ligusticum chuanxiong Hort, on wounds caused by diabetes. TMP transitioned macrophages to a pro-healing phenotype, leading to faster healing when combined with a HA hydrogel, minimizing inflammation, boosting angiogenesis, and improving collagen deposition [133]. Traditional wound dressings impede the healing of wounds in diabetics. This study created a novel in situ-forming hydrogel using CMCS and OHA through a Schiff base reaction, adding Tau for its anti-inflammatory effects. The hydrogel showed remarkable biocompatibility, improved cell migration, and lower inflammatory cytokines, positioning it as a promising choice for treating diabetic wounds (Fig. 23) [134].

Fig. 23.

Illustration of the CMCS-OHA-Tau hydrogel, its formulation, and application in diabetic rats, where it supports wound repair by reducing inflammation and enhancing angiogenesis. Reproduced with authorization from Elsevier [134]

Chronic wounds in diabetics are difficult to treat due to their sensitivity to infection, prolonged healing times, and elevated risks of disability and fatality, requiring new therapeutic approaches beyond traditional methods. A variety of hydrogel-based methodologies have been devised to tackle this problem. An injectable chitosan (CS) hydrogel (CCOD), synthesized via a Schiff base reaction involving chitosan-grafted chlorogenic acid (CS–CGA), oxidized hyaluronic acid (OHA), and deferoxamine (DFO), exhibited robust antibacterial, anti-inflammatory, antioxidant, and angiogenic properties, along with adaptable injectability to accommodate irregular wound geometries, facilitating personalized management of complex infections [135]. Another method employed tetramethylpyrazine (TMP), an alkaloid derived from Ligusticum chuanxiong Hort, integrated into a hydrogel composed of Bletilla striata polysaccharide (BSP) and hyaluronic acid (HA) (TMP-BSP-HA), which facilitated inflammation reduction, neovascularization, and collagen deposition in streptozocin-induced diabetic mice, markedly enhancing wound healing in comparison to commercial carboxymethylcellulose-based dressings [136]. Furthermore, a sophisticated technique integrated interferon-alpha (IFN-α) into double-network HA–collagen-like protein (CLP) hydrogels using genetic fusion or spy-chemistry ligation, with the latter exhibiting superior results in promoting cell survival, migration, and protein production [137]. In vivo, spy-chemistry ligated IFN-α-HA-CLP hydrogels shown significant enhancements in wound closure, elevated expression of COL-1α, CK-14, and α-SMA, and overall tissue regeneration relative to controls. These hydrogel systems collectively provide prospective therapeutic platforms that integrate antibacterial, anti-inflammatory, angiogenic, and pro-healing properties to enhance diabetic wound repair efficiently.

Chronic diabetes wounds and diabetic foot ulcers are challenging to manage due to ongoing inflammation, infection, and compromised angiogenesis, necessitating the development of sophisticated multifunctional wound dressings that facilitate both full healing and functional remodeling. Dynamic hyaluronic acid (HA) hydrogels were developed utilizing boronate and coordination chemistry to provide injectability, self-healing properties, detachment, wound-responsive degradation, and regulated H₂S release. These hydrogels proficiently polarized macrophages from the M1 to M2 phenotype, controlled inflammatory cytokines and associated mRNA expression, and synergistically regulated inflammation through ROS removal, H₂S release, and Zn²⁺ signalling [138]. The primary formulation, HTZS, significantly improved angiogenesis-related pathways and metabolic processes, facilitating substantial neovascularization, re-epithelization, collagen-I deposition, and hair follicle regeneration, thus accomplishing both structural healing and functional remodeling of diabetic wounds. A polyvinyl alcohol–hyaluronic acid composite hydrogel (PTKH), enhanced with tannic acid and silicate, was created as a comprehensive injectable system. Following injection, PTKH experienced an in situ sol–gel transition, resulting in the formation of a sticky, protective wound dressing with adjustable rheological, mechanical, and swelling characteristics [139]. It facilitated ROS scavenging, exhibited antimicrobial properties, and created a cell-supportive milieu, markedly enhancing angiogenesis, epithelization, and diminishing inflammation and infection in animal models. Collectively, these sophisticated hydrogel platforms underscore the promise of multifunctional and dynamic biomaterials to regulate inflammation, angiogenesis, and metabolism, therefore facilitating efficient healing and functional regeneration in chronic diabetic wounds.

In addition to its current applications in wound healing, infection control, and modulation of inflammation, further exploration of HA in diabetes mellitus could focus on its potential to regulate systemic metabolic dysfunction, including improving insulin sensitivity, protecting pancreatic β-cells from oxidative stress, and modulating adipose tissue inflammation to alleviate insulin resistance. Investigating HA-based carriers for the targeted delivery of antidiabetic drugs, growth factors, or gene therapies could enhance therapeutic precision and reduce side effects. Moreover, leveraging HA’s ability to interact with CD44 and other receptors may enable novel strategies for tissue regeneration beyond skin repair, such as promoting vascular and neural regeneration in diabetic complications like neuropathy or retinopathy. The integration of HA with bioelectronic or smart responsive systems (glucose-triggered release platforms) could also open pathways for real-time regulation of glucose levels and inflammatory microenvironments, offering multifunctional and patient-tailored therapeutic options for comprehensive diabetes management.

Neurological diseases

Lf/PBA-modified hyaluronic acid nanogels linked via disulfide bonds (Lf-DOX/PBNG) were designed for reduction-sensitive, dual-targeting glioma treatment, showing increased DOX release in high glutathione conditions, superior cytotoxicity, cellular absorption, and brain permeability compared to DOX solution and other nanogel types, as well as significantly enhanced pharmacokinetics and brain retention [140]. A dual-enzymatic crosslinking technique was utilized to create an injectable HT/HGA hydrogel, showcasing biocompatibility, antioxidant characteristics, and the ability to reduce neuroinflammation for treating TBI. This hydrogel operates by eliminating ROS, stimulating the Nrf2/HO-1 pathway, encouraging M2 microglia polarization, reducing proinflammatory factors, protecting BBB, boosting neurogenesis, and enhancing motor skills, learning, and memory functions [141]. PENPs based on HA/CS were developed for the delivery of CUR, showing stability, high encapsulation efficiency, extended drug release, and notable dose-dependent cytotoxicity towards C6 glioma cells, with cellular uptake promoted by different endocytic pathways [142]. A chemoimmunotherapy based on bioresponsive HA was developed by linking DOX and CpG to HA, enhancing GBM treatment through the promotion of immunogenic cell death, the transformation of M2-like microglia into an antitumor M1 phenotype, and the activation of CD8 + T cell responses, leading to over 66% long-term survival in a GBM model, highlighting its promise for brain cancer treatment [143]. A hydrogel made of hyaluronic acid was developed to draw in and trap leftover GBM cells using the chemoattractant hUII, and then eliminate them with doxorubicin. This method demonstrated successful GBM cell movement, hydrogel penetration, and significant cytotoxicity, highlighting its potential for targeted GBM therapy [144].

A blended bioink containing GelMA, AlgMA, and HA was developed for 3D bioprinting of NPCs, showing high cell viability ( ~ 80%), neuronal differentiation, and functional network establishment, thereby positioning it as a potential material for in vitro neuronal models [145]. A microemulsion combining a bifunctional AS1411 aptamer/hyaluronic acid co-delivering shikonin and docetaxel (AS1411/SKN&DTX-M) was developed for targeted therapy of glioma, successfully crossing the blood-brain barrier, enhancing drug delivery and cytotoxic effect, blocking cancer stem cell spheroid development, and significantly lowering glioma growth, offering a potential strategy for combined antiglioma treatment [146]. An injectable hyaluronic acid hydrogel, cross-linked with horseradish peroxidase and galactose oxidase, was developed for addressing TBI. The hydrogel that enclosed BMS and NGF improved neural cell survival, adjusted neuroinflammation, and promoted neurological recovery, thereby accelerating healing in a TBI animal model [147]. The hyaluronated CIT-HA*TBLs formulation, comprising PL, Sp 60, and SDC, yielded spherical nanoparticles (178.94 ± 12.4 nm) with high entrapment efficiency (74.92 ± 5.54%) and prolonged CIT release (81.27 ± 3.8%), showing significant therapeutic effects in vivo and ex vivo evaluations [148]. Scientists created hyaluronic acid-coated transfersomes (DPZ-HA-TFS) to deliver DPZ intranasally, improving brain targeting and minimizing gastrointestinal side effects in Alzheimer’s treatment. The formulation demonstrated a vesicle size of 227.5 nm, an entrapment of 75.83%, and a cumulative release of 37.94% after 8 h, showing notable nasal mucosal penetration and confirmed nontoxicity, suggesting a promising non-invasive delivery approach for DPZ [149]. The study created coassembled nanoparticles made of chitosan and hyaluronic acid (CHG NPs) to detect and inhibit β-amyloid (Aβ) fibrillogenesis, which is crucial in AD. CHG NPs exhibited notable stability, broad excitation and emission wavelengths, and robust attachment to Aβ aggregates. They exhibited increased red fluorescence when interacting with Aβ, enabling detection at 0.1 nM. Furthermore, CHG NPs efficiently inhibited Aβ fibril formation and were confirmed in vivo in Caenorhabditis [150].

Beyond the current advances in glioma therapy, traumatic brain injury (TBI) repair, and Alzheimer’s disease (AD) interventions, further exploration of HA in neurological diseases should consider its ability to regulate neuroinflammation through precise microglia and astrocyte modulation, as well as its potential to protect and restore blood–brain barrier integrity in neurodegenerative conditions. Investigating HA-based carriers for gene editing tools, neurotrophic factors, and anti-aggregation agents could provide targeted interventions for disorders such as Parkinson’s disease and Huntington’s disease. Additionally, exploiting HA’s receptor-mediated transport and tunable physicochemical properties could enhance non-invasive brain drug delivery systems, including nasal-to-brain pathways and responsive nanocarriers that release therapeutics in oxidative or inflammatory microenvironments. Expanding HA applications in neural tissue engineering, such as developing bioinks and scaffolds for 3D brain organoids and stem cell transplantation, may also accelerate the modeling and repair of complex neural networks. Finally, long-term studies on the interaction of HA-based materials with neuronal circuits and synaptic plasticity could deepen understanding of their therapeutic potential in restoring cognitive and motor functions across a broader spectrum of neurological disorders.

Cardiovascular diseases

Oxygen-producing injectable hydrogels, derived from natural polymers like GelMA and HA, and loaded with CAT, were developed for the treatment of AMI. The O2-releasing hydrogels, containing exosomes derived from mesenchymal stem cells (Exo-O2(+) hydrogel), emitted substantial amounts of oxygen for over five days in hypoxic conditions. The hydrogel in vitro simulated the release of paracrine factors from cardiac cells, such as rat cardiac fibroblasts, rat neonatal cardiomyocytes, and human umbilical vein endothelial cells, thus mimicking capillary activity. After four weeks of treatment in a rat AMI model, the Exo-O2(+) hydrogel significantly improved myocardial capillary density and cardiomyocyte division in the peri-infarct area compared to control subjects. The Exo-O2(+) hydrogel shows promise for cardiac regeneration and therapeutic applications [151]. HF remains a significant global public health issue and often occurs after MI. Cardiac fibrosis, caused by heart injury, impairs cellular activity and tissue repair. This research utilizes HA enriched with decorin to address cardiac fibrosis following myocardial damage. In vitro, microrods containing decorin displayed first-order release kinetics. Male rat models received intramyocardial injections of saline, microrods, decorin microrods, and free decorin to assess their effects on cardiac remodeling. Eight weeks after myocardial infarction, rats receiving decorin microrods exhibited a notable enhancement in EF (5.21% ± 4.29%) in contrast to saline (−4.18% ± 2.78%, p < 0.001) and free decorin (−3.42% ± 1.86%, p < 0.01). Furthermore, decorin microrods diminished cardiac fibrosis and cardiomyocyte hypertrophy relative to controls, suggesting advantageous ventricular remodeling [152]. HA-iMSC-EVs displayed typical characteristics of extracellular vesicles, such as distinct shape, size, and expression of marker proteins. In comparison to iMSC-EVs, HA-iMSC-EVs promoted tube formation and increased endothelial cell survival during oxidative stress, while also lowering ROS levels in cardiomyocytes. In THP-1 macrophages, both types of EVs reduced pro-inflammatory signaling; however, HA-iMSC-EVs were more successful at enhancing anti-inflammatory markers and lowering inflammasome proteins. Moreover, HA-iMSC-EVs decreased phospho-SMAD2 and fibrosis indicators in TGF-β1-activated cardiomyocytes. Proteomic analysis showed an increase in pathways associated with immune response and angiogenesis. The administration of HA-iMSC-EVs directly into the myocardium improved heart function, decreased remodeling, and increased capillary density in hearts after infarction [153].

DHV cross-linked with different molecular weights of OHA improved stability, hemocompatibility, and macrophage polarization. Middle-molecular-weight OHA scaffolds, additionally enhanced with RGD-PHSRN peptide, exhibited anti-calcification effects, promoted endothelial cell growth, and demonstrated improved recellularization in vivo [154]. An innovative catheter, AMCath, was developed to tackle challenges in delivering fast-gelling, covalently cross-linked hyaluronic acid hydrogels to the heart. The apparatus enabled the efficient delivery of hydrogels into the pig’s left ventricle, showing retention post-injection, although the mechanical properties were slightly reduced during passage through the catheter. Additionally, AMCath facilitated the delivery of hydrogels containing cardiopoietic stem cells while maintaining cell viability [155]. Injectable HA hydrogels were studied for their effects on LV remodeling, infarct expansion, and stiffness in a porcine infarct model over a 12-week duration after MI. MRI and finite element modeling were used to assess left ventricular structure, infarct thinning, and tissue deformation. The hydrogel treatment reduced left ventricular dimensions, improved ejection fraction, and increased wall thickness compared to the control group. Finite element simulations revealed that hydrogel treatment improved infarct stiffness over a 12-week period, highlighting the role of MRI and finite element modeling in evaluating the impact of injectable hydrogel therapies on heart function after myocardial infarction [156]. The research evaluated the impact of peptide crosslinkers on matrix degradation and neovascular formation in HyA-based hydrogels. By integrating cell-adhesive peptides and MMP-degradable linkers, QPQGLAK hydrogels facilitated the growth of cardiac progenitor cells, increasing MMP, VEGF, and proteins associated with angiogenesis. This resulted in successful protein retention and enhanced vascular development following implantation in the hindlimbs of mice [157]. The effect of the RGD peptide (arginine-glycine-aspartate) on hMSCs within HA hydrogel was examined under both regular and ischemic conditions to assess its impact on cell viability and function. In standard conditions, RGD-modified HA significantly enhanced cell spreading and the release of VEGF and MCP-1 when compared to unmodified HA. In ischemic conditions, cell viability and protein secretion were similar for both RGD-modified and unmodified HA. Confocal imaging revealed reduced cell adhesion in both cases. Pre-culturing human mesenchymal stem cells in standard conditions before exposure to ischemic conditions improved cell adhesion, survival, and functionality. This study suggests that pre-treating cells with RGD-modified hydrogel may enhance viability and function in areas affected by ischemic damage, offering potential uses in cardiac tissue engineering [158]. A new hydrogel developed from ALG and HA containing Ly-PRF was designed to enhance MI treatment by releasing growth factors. In vitro studies revealed that the combination of ALG-HA with Ly-PRF hydrogel exhibited beneficial mechanical properties and release behaviors. When given to infarcted myocardium, it preserved cardiac function, promoted angiogenesis, increased vascular density, and improved conditions in both the infarcted area and surrounding regions. The hydrogel also influenced macrophage polarization and cardiac fibrosis. The autologous Ly-PRF in the hydrogel offers advantages such as safety, ease of obtaining, and cost-effectiveness [159].

A new approach for managing MI utilizes poly(lactic-co-glycolic acid) (PLGA) microparticles modified with human VE-cad-Fc fusion protein, which are mixed with hMSCs to create FMAs. This fusion protein enhances the paracrine role of MSCs. These FMAs are enclosed in an injectable hydrogel made of HA, created through a Schiff base reaction involving OHA and HHA. The OHA@HHA hydrogel with FMAs is injected into the damaged myocardium, improving the myocardial infarction environment by reducing inflammatory cytokines and increasing the release of angiogenic factors. Echocardiographic and histological studies reveal improved heart function, structure, and revascularization [160]. A microencapsulation method inspired by biomimicry is presented for the collection and growth of high-quality human iPSCs. This technique replicates the initial stages of blastocyst formation, where iPSC clusters are surrounded by a core rich in HA and encased by a hydrogel shell that resembles the zona pellucida. The generated pluripotent spheroids exhibit enhanced expression of pluripotency markers and successful cardiac differentiation, with HA being vital for maintaining cell quality during further cultivation [161]. BMSC were placed with silk fibroin/hyaluronic acid (SH) patches in rat hearts after MI to evaluate their impact on LV remodeling. Four groups were analyzed: Sham, MI, SH, and BMSC/SH. After eight weeks, SH and BMSC/SH patches exhibited good integration with slight immune reaction, demonstrating enhanced cardiac repair in SH and notable advantages in BMSC/SH, such as increased wall thickness, decreased apoptosis, and improved neo-vascularization [162].

Recent progress in the reprogramming and cardiac differentiation of human cells has not yet made the use of engineered myocardial tissue for treatment feasible, mainly because of the challenges in creating large, vascularized, contractile tissue patches containing clinically relevant matrix components. Traditional porous three-dimensional frameworks are insufficient because cardiomyocytes do not migrate. A thorough in situ hydrogelation system employing Alg and HyA was created. This method enables covalent hydrazone cross-linking of polysaccharides alongside living myocytes, permitting adjustable mechanophysical properties by altering derivatization and composition. The hydrogel facilitated the creation of contractile bioartificial cardiac tissue from newborn rat heart cells enriched with cardiomyocytes, mimicking native myocardium. The combination of HyA and pure human collagen I significantly increased contraction force compared to collagen by itself, making these hydrogels a crucial tool for enhancing the properties and efficacy of synthetic cardiac tissue for clinical heart muscle repair [163]. A 3D-printed patch composed of hCMPCs embedded in a HA/gel matrix was evaluated for its therapeutic effectiveness in addressing MI. The patch, composed of six printed layers, supported cell survival, growth, and differentiation. Transplantation into a mouse model of myocardial infarction led to a notable reduction in adverse remodeling and preservation of cardiac function, as demonstrated by MRI and histological assessment. The matrix promoted the extended survival and integration of hCMPCs, alongside an increase in cardiac and vascular differentiation markers over a 4-week duration [164]. O-HA reduced infarct size and apoptosis at the myocardial infarction site, improved myocardial angiogenesis, and supported the restoration of myocardial function in a mouse model of myocardial infarction. Additionally, o-HA promoted M2-type macrophage polarization, reduced the inflammatory response triggered by neutrophils, and accelerated myocardial functional recovery in vivo. Transcriptomic studies revealed that o-HA stimulated the synthesis of chemokines Ccl2 and Cxcl5, promoting macrophage polarization, and triggered the MAPK and JAK/STAT signaling pathways to produce a compensatory cardiac functional response [165]. Rebuilding cardiac tissue after a MI poses a significant challenge in tissue engineering. After ischemic injury, matrix remodeling and the formation of avascular scar tissue hinder cell engraftment and survival, limiting the effectiveness of cell replacement therapy. To address this problem, discrete microrods made of HA were developed to provide localized biochemical and biomechanical signals for cellular reprogramming and the reduction of cardiac fibrosis. The HA microrods, designed with varying stiffness, experienced degradation in the presence of hyaluronidase. In vitro, fibroblasts interacting with the microrods exhibited changes in proliferation, collagen production, and markers for myofibroblasts. When administered in a rat model of myocardial infarction, the HA microrods prevented thinning of the left ventricular wall and improved cardiac function six weeks after the infarction [166]. Transthoracic echocardiography demonstrated an 18.2% (P < 0.01) increase in ejection fraction in the gel-injected groups compared to the control group, nearly returning the ejection fraction to baseline (preoperative) levels. Histological analysis using H and E and Sirius red staining revealed reduced scarring and a 22.6% (P < 0.01) decrease in collagen deposition in the gel-injected group compared to the control group. VEGF staining showed a notable rise in new blood vessel formation in the hydrogel-injected groups compared to the control [167].

The rupture of susceptible plaques and ensuing thrombosis due to atherosclerosis are significant contributors to acute cardiovascular and cerebrovascular incidents, underscoring the critical necessity for an in-situ, noninvasive, sensitive, and molecularly focused detection method. CD44, a receptor prominently expressed on macrophage surfaces, was designated as the target for the molecular probe. HA, the ligand for CD44, was coupled to the surface of Gd2O3@MSN to create the MRI nanoprobe HA-Gd2O3@MSN for the targeted detection of atherosclerosis. The primary attributes of HA-Gd2O3@MSN were initially investigated. Biocompatibility was validated with CCK-8 assays, hemolysis assays, hematoxylin-eosin staining, and blood biochemical evaluations. The targeting capability was shown by laser confocal microscopy, cellular magnetic resonance imaging, flow cytometry, and immunohistochemistry. The in vivo targeting efficacy was also confirmed in a rabbit model of atherosclerosis [168]. Atherosclerosis, a lipid-induced inflammatory condition with significant global prevalence and mortality, can be managed by nanotherapeutic approaches that enhance medication delivery and biocompatibility. A biomimetic ROS-responsive hyaluronic acid-based nanocarrier (HSP) was engineered to encapsulate methotrexate (MTX), resulting in MTX-loaded nanoparticles (MTXNPs), which were subsequently coated with macrophage membranes to create MM/MTXNPs. These nanoparticles demonstrated superior biocompatibility, reactive oxygen species reactivity, and the capacity to escape macrophage clearance while specifically targeting inflamed endothelium cells. In vitro, MM/MTXNPs diminished lipid accumulation in foam cells, while in vivo, they exhibited increased accumulation at plaque sites and more potent therapeutic effects in inhibiting plaque progression compared to free MTX or MTXNPs, thereby establishing HSP as a promising platform for effective and biocompatible atherosclerosis treatment [169].

Isosorbide mononitrate (ISMN)-loaded liposomes (ISMN-LNPs) were encapsulated in an injectable composite hydrogel consisting of κ-carrageenan (κ-Car), hyaluronic acid (HA), and tannic acid (TA). The resultant hydrogel exhibited significant reactive oxygen species (ROS) scavenging ability, hence facilitating improved cell movement. The injection of ISMN-LNP-loaded hydrogel into the damaged hearts of rats resulted in substantial enhancements in cardiac function. Masson’s staining validated a decrease in myocardial infarct size and an augmentation in left ventricular wall thickness following myocardial infarction. Immunofluorescence labeling revealed increased expression of vascular hemophilic factor (VWF) and α-actinin, suggesting that the hydrogel system enhanced vascular proliferation and improved both systolic and diastolic cardiac function [170]. Natural products are highly esteemed in clinical therapy for their little toxicity and significant bioactivity, while the modification of biopolymers into nanostructures presents chances to improve their targeted efficacy. A nanoplatform was developed utilizing the multifunctional modification of β-cyclodextrin (β-CD) to encapsulate and transport the unstable medication (−)-epicatechin gallate (ECG) to atherosclerotic plaques. Acetalized cyclodextrin (PH-CD), sensitive to low pH conditions, and hyaluronic acid cyclodextrin, which targets the CD44 receptor on macrophage membranes, were produced from β-cyclodextrin and hyaluronic acid using acetalization and transesterification. The dual-carrier nanoparticles (Double-NPs) encapsulating ECG were synthesized by a solvent evaporation technique. These Double-NPs efficiently scavenged reactive oxygen species, promoted macrophage migration, reduced macrophage apoptosis, and suppressed aberrant proliferation and migration of vascular smooth muscle cells. In ApoE^–/– animals subjected to a high-fat diet, Double-NPs significantly accumulated in atherosclerotic plaques, decreasing plaque area, inflammatory infiltration, and instability [171].

MI continues to pose a significant global health challenge, and extracellular vesicles (EVs) originating from hyaluronic acid–primed induced mesenchymal stem cells (HA-iMSC-EVs) exhibit encouraging therapeutic promise. HA-iMSC-EVs displayed characteristic features of extracellular vesicles and exhibited superior effects relative to iMSC-EVs, including enhanced angiogenesis, improved endothelial cell survival under oxidative stress, decreased reactive oxygen species generation in cardiomyocytes, heightened anti-inflammatory activity in macrophages, and inhibition of fibrosis-related signaling. Proteomic study demonstrated an enrichment in pathways associated with immunology, extracellular matrix structure, angiogenesis, and cell cycle control. After intravenous or intramyocardial administration, HA-iMSC-EVs concentrated in the myocardium, with intramyocardial injection resulting in superior uptake. Functional and histological assessments demonstrated enhanced cardiac function, less necrosis and fibrosis, elevated capillary density, and increased viable myocardium, underscoring HA-iMSC-EVs as a formidable therapeutic approach for cardiac repair post-myocardial infarction [153].

Beyond current applications in myocardial infarction repair, cardiac fibrosis reduction, and angiogenesis promotion, future investigations of HA in cardiovascular diseases should explore its role in modulating immune–inflammatory responses that drive vascular remodeling and heart failure progression, particularly through targeted regulation of macrophage and fibroblast phenotypes. HA-based systems could also be leveraged for controlled delivery of cardioprotective peptides, RNA therapeutics, or gene-editing tools to restore cardiac function at the molecular level. Additionally, understanding how HA molecular weight, degradation products, and receptor interactions influence vascular tone, thrombosis, and endothelial homeostasis may open new strategies for treating hypertension and atherosclerosis. Integration of HA with smart biomaterials or bioelectronic devices capable of responding to ischemic or oxidative stress microenvironments could further enhance precision therapy. Finally, expanding HA’s applications into heart valve engineering, vascular graft coatings, and long-term regenerative patches may support durable structural repair and functional recovery in complex cardiovascular pathologies.

Conclusion

The comprehensive study and advancement of HA-based materials have showcased their impressive adaptability and capability in tackling various biomedical issues. HA’s distinct physicochemical attributes and biological roles have established it as a fundamental element in contemporary biomedical research, spanning from cancer treatment to inflammation management, wound repair, and tissue regeneration. The capability to adjust HA’s molecular weight, functionalize it with diverse molecules, and shape it into various forms like hydrogels, nanoparticles, and scaffolds has greatly improved its therapeutic uses. In cancer treatment, HA-based materials have demonstrated potential in specific drug delivery, defeating resistance mechanisms, and boosting the effectiveness of immunotherapies. In wound healing, HA-based products have shown greater effectiveness in facilitating tissue repair, minimizing inflammation, and improving angiogenesis. Moreover, HA’s function in managing oxidative stress and inflammation has been successfully utilized in addressing chronic inflammatory conditions. The advancement of intelligent drug delivery systems and bioactive scaffolds has broadened the possibilities of HA-based materials in tissue engineering and regenerative medicine. As investigations keep revealing new perspectives on the complex functions of HA, its uses in biomedical science are anticipated to expand, providing innovative approaches for therapeutic intervention and tissue regeneration. The progress in biomedical uses of hyaluronic acid-derived materials indicates a notable advancement in regenerative medicine and treatment approaches. The various uses of HA, spanning from cancer therapy to wound healing and inflammation management, emphasize its ability to tackle some of the most urgent medical issues we face today. The continued research and development activities in this field are expected to improve the therapeutic effectiveness and clinical usability of HA-based materials. As researchers keep investigating the complete possibilities of hyaluronic acid, it is expected that these substances will become more significant in creating advanced biomedical solutions, leading to enhanced patient outcomes and better quality of life.

The future perspectives on HA-based biomaterials point toward a paradigm shift in how we approach complex disease management, tissue regeneration, and personalized medicine. The next decade is likely to see the translation of HA’s multifunctional properties, anti-inflammatory, antioxidant, antibacterial, and regenerative into clinically approved therapies. With the rise of precision nanomedicine, HA-coated nanoparticles and hydrogels will continue to evolve as vehicles for targeted drug delivery, especially in oncology, where CD44 receptor-mediated targeting is showing consistent promise. Beyond cancer, the adaptability of HA to environmental cues such as pH, oxidative stress, and enzymatic degradation will enable smart, stimuli-responsive systems that can deliver drugs in a controlled, site-specific manner. This paves the way for highly efficient treatments with reduced systemic toxicity, a crucial need for diseases like osteoarthritis, inflammatory bowel disease, and chronic wounds. Additionally, integrating HA with emerging biofabrication techniques such as 3D bioprinting and tissue-engineered scaffolds will expand its role in regenerative medicine, enabling the repair of cartilage, neural tissue, and cardiovascular structures with unprecedented precision and biocompatibility. Moreover, the convergence of HA chemistry with bioinformatics, artificial intelligence, and gene editing holds immense potential. Smart HA-based biomaterials could be engineered not just as passive carriers but as dynamic therapeutic platforms that sense pathological microenvironments and adapt their behavior in real time. For example, hydrogels embedded with HA could serve as bioactive scaffolds that recruit stem cells, release bioactive factors on demand, and even modulate immune responses to promote scar-free healing. In neurology, where blood–brain barrier penetration remains a formidable challenge, HA-based nanogels may open avenues for non-invasive delivery of drugs and genetic material to treat Alzheimer’s disease, glioblastoma, and traumatic brain injuries. Furthermore, sustainability and green chemistry will influence future HA production methods, with microbial fermentation and recombinant techniques becoming mainstream to ensure high yield, consistency, and eco-friendliness. Overall, the future perspective emphasizes that HA will not remain a mere structural biomaterial but will increasingly serve as a multifunctional, bioresponsive therapeutic platform at the intersection of chemistry, biology, and medicine.

HA-based systems, despite their versatility and widespread biomedical applications, present several limitations that must be addressed before broader clinical translation. A major challenge is their inherent instability and susceptibility to enzymatic degradation by hyaluronidases, which can compromise therapeutic efficacy and reduce the duration of action in vivo. Their biological activity is highly dependent on molecular weight, with high-molecular-weight HA exerting anti-inflammatory effects while low-molecular-weight fragments can induce inflammation, meaning uncontrolled degradation may generate adverse responses. Moreover, HA’s strong hydrophilicity, while advantageous for tissue hydration and lubrication, often results in weak mechanical strength, poor structural stability, and rapid clearance, limiting its use in load-bearing tissues or long-term applications. Drug delivery systems based on HA also face difficulties with controlling release kinetics, ensuring efficient cellular uptake, and overcoming tumor heterogeneity, as not all cancer cells overexpress CD44 receptors targeted by HA conjugates. Additionally, large-scale production and chemical modification of HA to improve its stability, bioactivity, and multifunctionality can be complex, expensive, and variable in quality, raising translational barriers. Immunogenicity is generally low, but repeated administration or structural modifications may alter its biocompatibility profile. Furthermore, while HA-based hydrogels, nanoparticles, and scaffolds show promise in wound healing, inflammation management, and targeted therapies, their performance in vivo can differ significantly from in vitro results due to the complexity of biological environments, oxidative stress, and immune responses. Altogether, although HA-based systems represent a powerful platform in regenerative medicine and drug delivery, their clinical impact remains constrained by issues of stability, reproducibility, mechanical robustness, cost-effectiveness, and biological variability.

HA-based systems have emerged as highly promising tools in a wide spectrum of clinical applications due to their biocompatibility, biodegradability, and ability to interact with specific cellular receptors such as CD44, enabling both regenerative and therapeutic benefits across diverse medical fields. In oncology, HA-functionalized nanoparticles and hydrogels are being exploited for targeted drug delivery, photothermal and photodynamic therapies, and chemo-immunotherapy, as they selectively accumulate in CD44-overexpressing tumor cells, improving therapeutic efficacy while minimizing systemic toxicity. In wound healing, HA-based hydrogels, films, microneedles, and bioadhesives accelerate tissue repair by modulating inflammation, scavenging reactive oxygen species, promoting angiogenesis, and supporting extracellular matrix remodeling, with particular success demonstrated in chronic and diabetic wound models. In orthopedics and rheumatology, intra-articular injections of HA derivatives are widely used to restore lubrication, reduce pain, and slow cartilage degradation in osteoarthritis, while engineered HA-based hydrogels and microparticles enhance cartilage regeneration and protect chondrocytes from inflammatory and oxidative damage. Cardiovascular applications include HA-derived injectable scaffolds loaded with bioactive molecules or exosomes that improve angiogenesis, reduce fibrosis, and aid myocardial repair after infarction. In neurology, HA-based nanogels and hydrogels have been designed for brain-targeted delivery of chemotherapeutics, anti-inflammatory agents, and neurotrophic factors, offering strategies for glioblastoma management, traumatic brain injury recovery, and neurodegenerative disease treatment. Additionally, HA formulations are advancing in ophthalmology for corneal healing and intraocular surgery, in dentistry for periodontitis therapy and bone regeneration, and in dermatology and cosmetics for skin rejuvenation, hydration, and anti-aging interventions.

Author contributions

Li Wang, Writing-review editing; Writing-original draft; Fei Zhou, Conceptualization, Writing-review editing; Weimin Xie, Conceptualization, Writing-review editing.

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.