Natural bioactive compounds exhibit significant antioxidant and anti-inflammatory activities, offering a promising natural alternative or complement to current immunosuppressive therapies for ulcerative colitis (UC). However, achieving effective colon-targeted delivery of these compounds remains a significant challenge due to premature drug release and limited local retention. In this study, we present a nanoparticle-hydrogel composite system, BZH@HCE, designed to enhance the therapeutic efficacy of baicalein (BA) for UC treatment. Zein and oxidized hyaluronic acid-based nanoparticles (BZH) provide a high loading capacity for BA and prevent premature drug release in the upper gastrointestinal tract. BZH encapsulation within an epigallocatechin gallate (EGCG)-containing hydrogel matrix (HCE) further sustains BA release and amplifies its antioxidant and anti-inflammatory effects through synergistic action with EGCG. The adhesive hydrogel matrix ensures prolonged colon retention for up to 24 hours in colitis mice. In vivo studies using a dextran sulfate sodium-induced murine colitis model demonstrate that BZH@HCE significantly alleviates intestinal inflammation, promotes epithelial barrier repair, and shows excellent biocompatibility, outperforming both free BA and BZH nanoparticles. These findings position BZH@HCE as a versatile and effective platform for UC therapy, highlighting its potential as a natural, bioactive compound-based treatment.

Esophageal diseases, including esophageal cancer and gastroesophageal reflux disease, remain major clinical challenges because of limited therapeutic efficacy and frequent treatment-related complications. Systemic treatments often suffer from insufficient drug accumulation at the lesion site and undesirable off-target effects, whereas endoscopic submucosal dissection (ESD), despite its effectiveness for early-stage lesions, is frequently complicated by postoperative esophageal stricture. These limitations underscore the need for localized and multifunctional therapeutic strategies. Owing to their excellent injectability, tunable physicochemical properties, and favorable biocompatibility, polysaccharide-based hydrogels, including those derived from chitosan, alginate, hyaluronic acid, and cellulose, have emerged as promising biomaterials for esophageal applications. As drug delivery systems, they enable localized and sustained therapeutic delivery with stimuli-responsive release capabilities, thereby enhancing therapeutic efficacy while minimizing systemic toxicity. In ESD, these hydrogels serve not only as submucosal injection agents to provide stable and sustained mucosal elevation but also as wound dressings that facilitate tissue regeneration, inhibit excessive fibrosis, and reduce the risk of postoperative stricture. The current challenges and future directions for the clinical translation of polysaccharide hydrogel-based platforms are also discussed. Collectively, it provides a comprehensive framework for the rational design and clinical development of polysaccharide hydrogel-based platforms to address the unmet therapeutic needs of esophageal diseases.

Chronic wounds are complicated by multidrug-resistant infections, oxidative stress, and prolonged inflammation, where single-mode antibacterial therapies are often inadequate. Here, we present a self-adaptive forming composite hydrogel (HP-BA@AD) that integrates direct bactericidal activity with host immune modulation for phase-specific wound healing. The polymer hydrogel HP-BA is constructed via dynamic boronate ester crosslinking between butyrate-modified polyvinyl alcohol and phenylboronic acid-functionalized oxidized hyaluronic acid, ensuring rapid gelation and strong adhesion to irregular wound beds. To enable controlled copper release and minimize cytotoxicity, reactive oxygen species (ROS)-responsive alginate-dopamine/Cu microspheres (AD) are incorporated. Under oxidative stress, AD releases Cu2+/Cu+ to amplify ROS, thereby enhancing macrophage phagocytosis and exerting bactericidal effects. Concurrently, butyrate is gradually liberated in acidic and enzymatic environments, suppressing mTOR signaling and reshaping cytokine profiles to promote immunemediated bacterial clearance. The butyrate-rich hydrogel exhibits strong bio-adhesion through hydrophobic interactions, while hydrolysis leads to reduced adhesion and facile removal. In vitro and in vivo experiments demonstrates that HP-BA@AD efficiently eradicates S. aureus, alleviates inflammation, enhances wound closure, and improves angiogenesis and collagen remodeling, ultimately restoring functional skin tissue. By combining material-host antibacterial synergy, tunable bio-adhesion, and self-adaptive therapeutic responses, HP-BA@AD offers a versatile strategy for treating infected chronic wounds.

The development of oral drug delivery systems with colon-targeted release and high biocompatibility is of critical importance for the treatment of ulcerative colitis (UC), considering the chronic nature of the disease and the genetic susceptibility of patients. Herein, we report a composite delivery system (UA@PB/Gel) based on Generally Recognized As Safe (GRAS) materials, poly(vinyl alcohol) (PVA) and inulin, designed for colon-specific delivery of ursolic acid (UA). In this system, butyrate-conjugated PVA nanoparticles efficiently encapsulate UA and respond to colonic esterase, enabling the localized release of both UA and butyrate. Embedding these nanoparticles within an inulin hydrogel further enhances colonic retention and provides a sustained release. The composite system demonstrates efficient colon-targeting delivery, prolonged retention, and potent anti-inflammatory effects in vitro and in vivo. In a dextran sulfate sodium-induced colitis mouse model, UA@PB/Gel effectively alleviates colonic inflammation, restores epithelial barrier integrity, reduces proinflammatory cytokine expression, and modulates gut short-chain fatty acid levels, with minimal systemic toxicity. These results highlight the potential of the GRAS materials-based nanoparticle-hydrogel composite as a safe and effective therapeutic platform for UC.

The gut's inflammation is governed by the enteric nervous system, where enteric glial cells (EGCs) serve as essential intermediaries between the nervous and immune systems. During inflammation, elevated levels of S100 calcium-binding protein B (S100B) from hyperactive EGCs initiate a proinflammatory cascade by inducing the excessive production of reactive oxygen species (ROS) and proinflammatory molecules, including S100B itself, thus establishing a detrimental feedback loop. Herein, we develop a S100B inhibitor pentamidine (PTM)-loaded olsalazine-based nanoneedle, Zn2(Olsa)/PTM, to break this vicious cycle and alleviate ulcerative colitis. Zn2(Olsa)/PTM not only enhances the cytocompatibility of PTM but also reduces the level of excessive production of S100B and ROS in EGCs. To enhance colon-targeted delivery, Zn2(Olsa)/PTM is coated with an enteric polymer Eudragit L100-55 to create ZOP@Eud. The oral administration of ZOP@Eud considerably ameliorates disease severity and restores mucosal barrier integrity and immune homeostasis in a murine ulcerative colitis model, which is evidenced by heightened expression of tight junction proteins and reduced levels of colonic proinflammatory S100B and cytokines. These findings suggest that nanosystems targeting EGCs offer a promising approach for mitigating gut inflammation.

Copper-based nanoparticles have garnered significant interest in cancer therapy due to their ability to induce oxidative stress and cuproptosis in cancer cells. However, their antitumor effectiveness is constrained by the dynamic redox balance and the metabolic shift between oxidative phosphorylation and glycolysis. Here, a polydopamine-coated copper-α-ketoglutaric acid (α-KG) coordination polymer nanoparticle (CKPP) is designed for combined pyroptosis-cuproptosis cancer immunotherapy by amplifying reactive oxygen species (ROS) production and regulating cellular metabolism. The intracellular redox imbalance is achieved through the synergistic effects of α-KG-induced mitochondrial metabolic reprogramming, photothermally enhanced superoxide dismutase-like activity of polydopamine, and glutathione depletion by copper ions. The multifaceted redox modulation results in a substantial increase in intracellular ROS levels, triggering oxidative stress and subsequent pyroptosis in cancer cells. Furthermore, α-KG shifts cellular metabolism from glycolysis to oxidative phosphorylation, thereby enhancing cuproptosis induced by copper ions. The combination of ROS dyshomeostasis and glycolysis inhibition results in a potent enhancement of pyroptosis-cuproptosis-mediated cancer therapy. In a murine model of colorectal cancer, CKPP exhibited a remarkable anticancer effect, achieving a tumor inhibition rate of 96.3% and complete tumor eradication in two out of five cases. Overall, this bio-engineered metal-organic nanocomposite demonstrates significant potential for treating cancer through combined pyroptosis-cuproptosis cancer immunotherapy.

High performance is necessary for materials to repair load-bearing bones. The elastic moduli of conventional metals, such as stainless steel and titanium alloys, are significantly higher than those of human cancellous and cortical bones, leading to severe stress shielding effects and requiring secondary surgery for removal. The insufficient mechanical strength of biodegradable polymers or hydroxyapatite-blended biodegradable polymers limits their application in load-bearing bone repair. In this study, we developed bioactive glass fiber-reinforced biodegradable polymer composites for the repair of load-bearing bones. The biodegradable polymer matrix was a poly(epsilon-caprolactone)-b-poly(l-lactide) diblock copolymer. Bioactive glass 13-93 was melt-spun into continuous fibers and subsequently laminated with diblock copolymers through hot pressing. The melt-spinning of bioactive glass fibers and composite manufacturing were investigated. Composites with 30 wt% and 50 wt% glass fibers were prepared; mechanical testing revealed that the elastic modulus of the composite plates containing 50 wt% bioactive glass fibers was as high as approximately 5 GPa, which exceeded that of human cancellous bone and approached the range of cortical bone modulus. Biocompatibility tests revealed that the composites were not cytotoxic and promoted osteoblast mineralization. With the addition of bioactive glass fibers, the composites exhibited excellent antibacterial properties against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Thus, the bioactive glass fiber-reinforced PCL-PLLA composites are favorable for load-bearing bone repair.

Hemostasis is the initial step in wound healing, yet significant challenges, such as massive bleeding and infection, often arise. In this study, we developed amphiphilic biodegradable polyester-based segmented polyurethane (SPU) microspheres modified with epigallocatechin gallate (EGCG)-Ag nanoparticles and calcium-alginate cross-linking shell, combining blood absorption with the pro-coagulation properties of Ca2+ and the negative charge of EGCG for synergistic hemostatic effects across various stages of the coagulation cascade. The in vitro blood clotting time of the SPU@EAg@CaAlg microsphere (328.7 s) was reduced by half compared to the SPU microsphere (685.0 s). SPU@EAg@CaAlg exhibited a reduced hemostatic time and blood loss in three rat hemostatic models. Additionally, EGCG-Ag nanoparticles imparted strong antibacterial and anti-inflammatory properties both in vitro and in vivo. In vivo infected wound model demonstrated that SPU@EAg@CaAlg effectively eliminated bacteria and reduced the levels of pro-inflammatory factors, thereby promoting wound healing. Thus, the modified SPU microspheres present a promising candidate for effective hemostatic applications.

Rapid and effective hemostasis is a necessary prerequisite for the management and repair of wounds. Natural polysaccharide-based hydrogel dressings are attractive in hemostasis and wound repair. In this review, the physiological mechanism of hemostasis and the design rationale of polysaccharide hydrogels from a physiochemical perspective is summarized. Then, the recent progress of multifunctional hemostatic polysaccharide hydrogel wound dressings that are characterized by high antibacterial activity, a high degree of tissue adhesion, good biocompatibility, and tunable swelling and degradation properties is reported. Finally, the personal perspectives on the current challenges and future developments of polysaccharide-derived hemostatic hydrogels are proposed.

Triple-negative breast cancer (TNBC) poses significant therapeutic challenges due to its metabolic plasticity and immunosuppressive microenvironment. In this study, we present a sequential drug release hydrogel system (SeqGel) that reprograms tumor metabolism and modulates the immune landscape to suppress TNBC growth and metastasis. The poly(ethylene glycol)-based injectable hydrogel system could enable tunable biodegradation within 48 h to ensure repeated peritumoral administration and localized controlled drug release. Specifically, water-soluble small molecular dichloroacetate is rapidly released to redirect tumor cell metabolism from glycolysis to oxidative phosphorylation, thereby reducing lactic acid accumulation, restricting glucose uptake, and enhancing the susceptibility of cancer cells to mitochondrial damage. This is followed by the sustained release of pH-sensitive, copper complex-loaded polymeric nanoparticles PED@tCu, which facilitates efficient intracellular delivery and targeted mitochondrial localization, specifically impairing the function of complex II. Mechanistically, the ordered metabolic intervention enhances antitumor immunity by activating the AMPK pathway, promoting PD-L1 degradation, and upregulating MHC I to improve antigen presentation. In 4T1 subcutaneous tumor models, SeqGel effectively suppressed tumor growth and markedly reduced lung and lymph node metastases by promoting CD8+ T cell infiltration and depleting regulatory T cells. This study establishes a paradigm for metabolic-immune synergy, offering a promising strategy for targeting aggressive cancers through chrono-metabolic immunotherapy.

Injectable facial fillers such as Sculptra® stimulate collagen regeneration to fill wrinkles; however, the collagen regeneration is not satisfactory due to the slow emergence of filling effect. In this study, we designed a regenerative dermal filler to provide both immediate and long-lasting filling effects. A hydrogel matrix composed of crosslinked hyaluronic acid (HA) and collagen was engineered to encapsulate porous poly(L-lactide) (PLLA) microspheres and tranexamic acid (TXA). The hydrogel matrix was administered via intradermal injection to achieve wrinkle filling. TXA is released to exert skin-whitening effects, while the porous PLLA microspheres and their degradation product, lactic acid, continuously stimulate collagen regeneration over an extended period. Facial volume increased immediately following hydrogel injection. Large amounts of new Type I and Type III collagen are generated. The porous structure of PLLA microspheres facilitated the 'penetrating growth' of collagen fibers, which effectively filled facial depressions and smoothed wrinkles. Overall, the HA/collagen composite hydrogel filler exhibited excellent esthetic effects.

Epigallocatechin gallate (EGCG)-based nanosystems have garnered significant attention for their ability to alleviate inflammation due to their excellent anti-inflammatory properties and enhanced drug delivery capabilities. However, the degradation of EGCG in strongly acidic environments poses a challenge for potential administration, particularly in oral formulations, where gastric resistance is essential. In this study, we develop a "disintegration and reorganization" strategy to create acid-resistant antioxidant nanoparticles (EGA NPs) based on EGCG and 5-aminosalicylic acid (5-ASA) for mitigating inflammation in colitis and acute kidney injury. At acidic pH, the ester bond in EGCG breaks down, producing two building blocks. These, together with 5-ASA and formaldehyde, form oligomers through a combination of phenol-aldehyde condensation and the Mannich reaction. The resulting oligomers self-assemble into EGA NPs, which exhibit significant stability under both acidic and neutral pH conditions. This stability makes them suitable for oral administration, allowing them to withstand harsh gastric conditions, as well as for intravenous injection. Importantly, these oligomers retain the antioxidant and anti-inflammatory properties of EGCG, effectively scavenging reactive oxygen species and reducing intracellular oxidative stress. Additionally, EGA shows potential as a drug carrier, efficiently loading the anti-inflammatory agent curcumin (Cur) to form Cur@EGA NPs. In vivo studies demonstrate the efficacy of Cur@EGA and EGA in alleviating acute colitis and kidney injury following oral and intravenous administration, respectively. These nanoparticulate formulations exhibit superior inflammation reduction compared to free Cur in vivo. Overall, our findings introduce a novel acid-resistant nanoplatform based on EGCG for the treatment of acute inflammation.

Inflammatory bowel disease (IBD) is a chronic and refractory condition characterized by disrupted epithelial barrier, dysregulated immune balance, and altered gut microbiota. Nano-enabled interventions for restoring gut homeostasis have the potential to alleviate inflammation in IBD. Herein, we developed a combination of olsalazine (Olsa)-based nanoneedles and microbiota-regulating inulin gel to reshape intestinal homeostasis and relieve inflammation. The Olsa-derived nanoneedles exhibited reactive oxygen species scavenging ability and anti-inflammatory effects in lipopolysaccharide-simulated macrophages. The composite of nanoneedles and inulin gel (Cu2(Olsa)/Gel) displayed a macroporous structure, improved bio-adhesion, and enhanced colon retention after oral administration. Mechanistically, the composite effectively downregulated pro-inflammatory cytokine levels and promoted epithelial barrier repair through anti-inflammatory and antioxidant therapies, resulting in significant alleviation of colitis in three animal models of IBD. Furthermore, analysis of gut microbiota revealed that Cu2(Olsa)/Gel treatment increased the diversity of intestinal microflora and decreased the relative abundance of pathogenic bacteria such as Proteobacteria. Overall, this study provides a self-delivering nanodrug and dietary fiber hydrogel composite for IBD therapy, offering an efficient approach to restore intestinal homeostasis.

Oral cancer is a significant global health challenge, with conventional treatments often resulting in substantial side effects and limited effectiveness. Phototherapy, encompassing photodynamic and photothermal therapy, presents a promising alternative by selectively targeting and destroying cancer cells with minimal systemic toxicity. However, issues such as insufficient light penetration and limited tumor specificity have restricted their clinical use. Recent advancements in nanosystems have addressed these challenges by enhancing the solubility, stability, and tumor-targeting capabilities of phototherapy agents. This review delves into the latest advancements in phototherapeutic nanosystems for oral cancer, focusing on the design of innovative nanoformulations and targeted delivery strategies. Additionally, it summarizes recent approaches to enhance the efficacy of photodynamic therapy for oral cancer and examines phototherapy-based combination treatments. These advancements hold the promise of significantly improving treatment outcomes while minimizing side effects in oral cancer therapy.

The healing of infected wounds is challenging for patients. In this paper, a hybrid hydrogel with strong tissue adhesion, self-healing, and antibiosis without antibiotics was developed as a dressing to promote the healing of infected chronic wounds. Acrylamide (PAM) was polymerized with N,N-methylene bis(acrylamide) (BIS) as the substrate, and self-assembled nanoparticles of carboxymethyl chitosan and chlorin e6 (CMCS/Ce6 NPs) trapped with magnesium (Mg2+) ions were dispersed in the hydrogel substrate. CMCS/Ce6 NPs provided favorable photodynamic antibiosis via the production of reactive oxygen species (ROS) under NIR irradiation. The hybrid hydrogels exhibited excellent self-healing properties, diverse adhesion, and biocompatibility. The in vivo results indicated that the hybrid hydrogel accelerated wound healing significantly via comprehensive factors of photodynamic antibiosis of CMCS/Ce6 NPs, cell proliferation promotion by Mg2+, good bioadhesion, and moisture retention of the PAM hydrogel, which promoted collagen deposition and blood vessel maturation.

A mitochondrial targeting copper dithiocarbamate induces intense immunogenic cuproptosis in cancer cells and macrophage M1 polarization. This emphasizes the potential of mitochondrial targeting cuproptosis inducers in cancer immunotherapy.

Negative pressure wound therapy (NPWT) is effective in repairing serious skin injury. The dressing used in the NPWT is important for wound healing. In this paper, we develop biodegradable amphiphilic polyurethanes (PUs) and fabricate the PUs into sponges as wound dressings (Bi@e) with Janus pore architectures for NPWT. The Bi@e is adaptive to all the stages of the wound healing process. The Janus Bi@e sponge consists of two layers: the dense hydrophobic upper layer with small pores provides protection and support during negative pressure drainage, and the loose hydrophilic lower layer with large pores absorbs large amounts of wound exudate and maintains a moist environment. Additionally, antibacterial agent silver sulfadiazine (SSD) is loaded into the sponge against Escherichia coli and Staphylococcus aureus with a concentration of 0.50 wt%. The Janus sponge exhibits a super absorbent capacity of 19.53 times its own water weight and remarkable resistance to compression. In a rat skin defect model, the Janus Bi@e sponge not only prevents the conglutination between regenerative skin and dressing but also accelerates wound healing compared to commercially available NPWT dressing. The Janus Bi@e sponge is a promising dressing for the NPWT.

Immune checkpoint blockade therapy provides a new strategy for tumor treatment; however, the insufficient infiltration of cytotoxic T cells and immunosuppression in tumor microenvironment lead to unsatisfied effects. Herein, we reported a lipid/PLGA nanocomplex (RDCM) co-loaded with the photosensitizer Ce6 and the indoleamine 2,3-dioxygenase (IDO) inhibitor 1MT to improve immunotherapy of colon cancer. Arginine-glycine-aspartic acid (RGD) as the targeting moiety was conjugated on 1,2-distearoyl-snglycero-3-phosphoethanolamine lipid via polyethylene glycol (PEG), and programmed cell death-ligand 1 (PD-L1) peptide inhibitor DPPA (sequence: CPLGVRGK-GGG-d(NYSKPTDRQYHF)) was immobilized on the terminal group of PEG via matrix metalloproteinase 2 sensitive peptide linker. The Ce6 and 1MT were encapsulated in PLGA nanoparticles. The drug loaded nanoparticles were composited with RGD and DPPA modified lipid and lecithin to form lipid/PLGA nanocomplexes. When the nanocomplexes were delivered to tumor, DPPA was released by the cleavage of a matrix metalloproteinase 2-sensitive peptide linker for PD-L1 binding. RGD facilitated the cellular internalization of nanocomplexes via av beta 3 integrin. Strong immunogenic cell death was induced by 1O2 generated from Ce6 irradiation under 660 nm laser. 1MT inhibited the activity of IDO and reduced the inhibition of cytotoxic T cells caused by kynurenine accumulation in the tumor microenvironment. The RDCM facilitated the maturation of dendritic cells, inhibited the activity of IDO, and markedly recruited the proportion of tumor-infiltrating cytotoxic T cells in CT26 tumor-bearing mice, triggering a robust immunological memory effect, thus effectively preventing tumor metastasis. The results indicated that the RDCM with dual IDO and PD-L1 inhibition effects is a promising platform for targeted photoimmunotherapy of colon cancer.

Natural remedies are gaining attention as promising approaches to alleviating inflammation, yet their full potential is often limited by challenges such as poor bioavailability and suboptimal therapeutic effects. To overcome these limitations, we have developed a novel nano-antioxidant (EK) based on epigallocatechin gallate (EGCG) aimed at enhancing the oral and systemic bioavailability, as well as the anti-inflammatory efficacy, of curcumin (Cur) in conditions such as acute colon and kidney inflammation. EK is synthesized using a straightforward Mannich reaction between EGCG and L-lysine (K), resulting in the formation of EGCG oligomers. These oligomers spontaneously self-assemble into nanoparticles with a spherical morphology and an average diameter of approximately 160 nm. In vitro studies reveal that EK nanoparticles exhibit remarkable radical-scavenging capabilities and effectively regulate redox processes within macrophages, a key component in the body's inflammatory response. By efficiently encapsulating curcumin within these EK nanoparticles, we create Cur@EK, a formulation that demonstrates a synergistic anti-inflammatory effect. Specifically, Cur@EK significantly reduces the levels of pro-inflammatory cytokines TNF-alpha and IL-6 while increasing the anti-inflammatory cytokine IL-10 in lipopolysaccharide-stimulated macrophages, highlighting its potent anti-inflammatory properties. When administered either orally or intravenously, Cur@EK shows superior bioavailability compared to free curcumin and exhibits pronounced anti-inflammatory effects in mouse models of ulcerative colitis and acute kidney injury. These findings suggest that the EK nano-antioxidant platform not only enhances the bioavailability of curcumin but also amplifies its therapeutic impact, offering a promising new avenue for the treatment and management of inflammation in both oral and systemic contexts.