Biomaterials最新文献

{"title":"Bone microenvironments-regulated biomaterials boost osteonecrosis therapy","authors":"Hang Dong ,&nbsp;Tongtong Zhu ,&nbsp;Yirong Sun ,&nbsp;Jiazhen Yang ,&nbsp;Guangyao Liu ,&nbsp;Guoliang Wang ,&nbsp;Jianxun Ding","doi":"10.1016/j.biomaterials.2025.123921","DOIUrl":"10.1016/j.biomaterials.2025.123921","url":null,"abstract":"<div><div>Several pathological mechanisms, including vascular endothelial cell injury, osteocyte apoptosis, and excessive osteoclast activation, drive osteonecrosis. The disease progression is further exacerbated by disrupted bone remodeling, immune system dysregulation, and impaired regeneration capacity of blood vessel and bone. In weight-bearing joints, progressive subchondral bone deterioration often leads to joint collapse, resulting in chronic pain, stiffness, and disability. Early intervention, typically involving core decompression combined with bone grafting, is essential to prevent irreversible joint damage. Due to the limited availability of autologous bone, research has increasingly focused on developing advanced artificial bone substitutes. This review systematically summarizes current biomaterial-based strategies for treating osteonecrosis, emphasizing innovative approaches that enhance vascular regeneration and osteogenesis while simultaneously suppressing osteoclast activity and modulating immune responses. It also provides an overview of osteogenic biomaterial fabrication and the mechanisms by which biomaterials mediate tissue regeneration, emerging trends in bioactive material development, and potential strategies for advancing next-generation biomaterials.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123921"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Self-assembled microparticle hydrogel scaffolds to construct artificial tertiary lymphoids for enhanced CAR-T cell therapy against solid tumors","authors":"Qiaofeng Li ,&nbsp;Zhisheng Xiao ,&nbsp;Bo Liu ,&nbsp;Yuchun Xu ,&nbsp;Chunjie Wang ,&nbsp;Mingkang Li ,&nbsp;Yuzhe Wu ,&nbsp;Chenxi Yin ,&nbsp;Wenzhuo Yu ,&nbsp;Zhuang Liu ,&nbsp;Yu Chao","doi":"10.1016/j.biomaterials.2025.123976","DOIUrl":"10.1016/j.biomaterials.2025.123976","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR)-T cell therapy while demonstrating remarkable efficacies in treating hematologic malignancies, has encountered challenges in solid tumor treatment, partly due to the limited intratumoral infiltration of effective immune cells and thus inefficient interactions between different immune cell types inside those tumors. Herein, we develop an injectable scaffold based on hydrogel microparticles (HMPs) with opposite charges to replicate tertiary lymphoid structures (TLSs) within the tumor microenvironment. With encapsulation of immune-stimulating cytokines inside HMPs and loading of both T cells and B cells between HMPs in the scaffold, the artificial TLSs after intratumoral injection could not only serve as a depot of immunostimulants, but also promote intercellular interactions between B and T lymphocytes to support continuous T cell expansion and activation. As demonstrated in several tumor models, our artificial TLSs loaded with both CAR-T cells and B cells after intratumoral injection could not only effectively suppress local tumors, but also present remarkable abscopal effects to inhibit distant tumors, presenting greatly enhanced therapeutic performance compared to conventional CAR-T therapy. Our work thus presents a novel strategy to improve the efficacy of T-cell-therapies against solid tumors based on immune-activating cell-loaded injectable hydrogel scaffold as artificial TLSs.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123976"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-targeted co-assembled nanosystem with multimodal mitochondrial DNA level control to alleviate inflammation and promote chronic wound healing","authors":"Xueyan Mao ,&nbsp;Chuanwen Wang ,&nbsp;Shufan Yu ,&nbsp;Kai Zhang ,&nbsp;Zheng Wang ,&nbsp;Jing Du ,&nbsp;Ying Kong ,&nbsp;Alberto Bianco ,&nbsp;Shaohua Ge ,&nbsp;Baojin Ma","doi":"10.1016/j.biomaterials.2026.123981","DOIUrl":"10.1016/j.biomaterials.2026.123981","url":null,"abstract":"<div><div>Mitochondrial dysfunction, particularly when associated with the mitochondrial DNA (mtDNA) activated cGAS-STING signaling pathway, represents a key pathogenic mechanism contributing to excessive inflammation. Therapeutic targeting of mitochondrial homeostasis coupled with precise modulation of mtDNA release emerges as a promising yet underexplored strategy to suppress pathological inflammation and promote chronic wound healing. Herein, epigallocatechin gallate-quercetin co-assembled nanoparticles (EQ NPs) were engineered to inhibit mtDNA-mediated inflammatory cascades through mitochondria-targeted multimodal mtDNA level control. Primarily, EQ NPs reduced the formation of oxidized mtDNA fragments (Ox-mtDNA). Then, EQ NPs inhibited the excessive opening of the mitochondrial permeability transition pore, preventing Ox-mtDNA cytoplasmic leakage. Subsequently, the escaped mtDNA fragments were neutralized by EQ NPs through polyphenol-mediated adsorption. Finally, mitophagy was upregulated to selectively eliminate damaged mitochondria. This well-designed strategy significantly inhibited the activation of the mtDNA-mediated cGAS-STING pathway, relieved the release of inflammatory factors, and promoted anti-inflammatory phenotype polarization of macrophages. In vivo, EQ NPs promoted chronic wound healing by bacteriostasis, anti-inflammation, immunomodulation, and accelerated angiogenesis. Overall, the study establishes a sequential mitochondrial quality control paradigm in which the inflammatory cascade is interrupted by multimodal and full-chain mtDNA scavenging, providing a promising candidate for the treatment of inflammatory diseases and chronic wound healing.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123981"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced MSC spheroid adhesion on 3D-printed leaf-stacked scaffolds for functional tracheal regeneration","authors":"Sang-Yoon Han ,&nbsp;Jae Keun Park ,&nbsp;Ji Suk Choi ,&nbsp;Eun Ji Jeong ,&nbsp;Min Rye Eom ,&nbsp;Ji Min Seok ,&nbsp;Min Ji Kim ,&nbsp;Su A. Park ,&nbsp;Se Heang Oh ,&nbsp;Seong Keun Kwon","doi":"10.1016/j.biomaterials.2026.123982","DOIUrl":"10.1016/j.biomaterials.2026.123982","url":null,"abstract":"<div><div>Reconstruction of segmental tracheal defects using three-dimensional (3D)-printed scaffolds remains a formidable challenge. While polycaprolactone (PCL) is widely utilized for its mechanical integrity, its inherent hydrophobicity limits cellular adhesion and tissue integration. In this study, we developed a 3D-printed PCL tracheal scaffold featuring a Leaf-Stacked Structure (LSS) and evaluated a spatially organized Mesenchymal Stem Cell (MSC) delivery strategy for functional regeneration. MSC spheroids were employed to overcome the limitations of monolayer cells, as their 3D configuration creates an internal hypoxic core that upregulates angiogenic and anti-inflammatory genes, thereby maximizing paracrine-mediated tissue repair. In vitro analyses, including cell adhesion assays and indirect co-culture systems, demonstrated that the LSS topography significantly enhanced the adhesion of both monolayer MSC and spheroids compared to plain PCL. Furthermore, MSC spheroids markedly promoted the proliferation and migration of human small airway epithelial cells. Based on these findings, we compared five experimental groups in a rabbit tracheal defect model: (1) Native, (2) No MSC, (3) Inner MSC (monolayer), (4) Outer spheroid, and (5) Dual group (combined inner monolayer and outer spheroids). In vivo, the Dual group exhibited the most robust mucosal regeneration, alongside an immunomodulatory shift toward increased M2/M1 macrophage ratios. Although neovascularization was prominent at MSC implantation sites, lineage analysis via β2-microglobulin tracking revealed that vessel-forming cells were primarily host-derived. This confirms that implanted MSC survived for 14 weeks and orchestrated regeneration predominantly through paracrine mechanisms.</div><div>Collectively, the integration of LSS topography and spatially organized MSC represents a promising synergistic strategy for functional tracheal reconstruction.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123982"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Duo-nano exosome encapsulating hydrogel boosts wound healing across xenogenic and allogenic models","authors":"Bibi S. Subhan ,&nbsp;Sydney E. Hanson ,&nbsp;Dianny Almanzar ,&nbsp;Juan F. Cortes Troncoso ,&nbsp;Priya Katyal ,&nbsp;Jonathan W. Sun ,&nbsp;Hao-Wei Shih ,&nbsp;Tamara Mestvirishvili ,&nbsp;Michael Meleties ,&nbsp;Fernando Arias ,&nbsp;Andrew Wang ,&nbsp;Kelly Ruggles ,&nbsp;Igor Dolgalev ,&nbsp;Paolo Mita ,&nbsp;Jin Kim Montclare ,&nbsp;Piul S. Rabbani","doi":"10.1016/j.biomaterials.2025.123953","DOIUrl":"10.1016/j.biomaterials.2025.123953","url":null,"abstract":"<div><div>Chronic wounds, especially in diabetic patients, pose a significant clinical challenge due to impaired microvasculature and delayed healing. This study presents Exo-Q, a novel thermoresponsive hydrogel formed by co-gelation of engineered Q protein nanofibers with exosomes, a class of vesicular intercellular communication mediators. Exo-Q transitions from a gel to a viscoelastic solution at physiological temperature, enabling localized, topical delivery of exosomes with an initial burst release followed by sustained release. In a diabetic mouse wound model, Exo-Q effectively delivered human bone marrow multipotent stromal cell-derived exosomes directly to the wound bed, where they accumulated in endothelial cells of granulation tissue without detectable systemic distribution. Exosomes produced under stringent and replicable cell culture conditions consistently carried biomacromolecular cargo enriched for miRNAs with validated targets in angiogenesis-associated genes, indicative of their therapeutic potential. Topical application of Exo-Q resulted in extensive neovascularized granulation tissue, significantly accelerating wound closure to levels comparable to non-diabetic wounds. Importantly, the hydrogel’s modular design maintained the functional integrity of Q protein nanofibers and exosomes, demonstrating compatibility with full-thickness human wounds. This platform allows for tailored customization to address critical stages of diabetic wound healing while ensuring efficacy at low dosages, potentially enabling patient-administered treatment. By leveraging advanced biomaterials, Exo-Q advances the therapeutic efficacy of exosome-based interventions for diabetic wounds, offering a localized, non-invasive solution to chronic, non-healing wounds. This innovative hydrogel platform represents a modular therapeutic strategy with significant potential for clinical applications in regenerative medicine.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123953"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered Needlepatch for the treatment of acute kidney injury","authors":"Xingli Zhao ,&nbsp;Xiaochen Li ,&nbsp;Lang He ,&nbsp;Xin Gong ,&nbsp;Yanhong Wang ,&nbsp;Lin Chen ,&nbsp;Hao Tian ,&nbsp;Yeqin Wang ,&nbsp;Xinrong Xu ,&nbsp;Tai Sheng ,&nbsp;Min Liu ,&nbsp;Junxuan Li ,&nbsp;Di Liu ,&nbsp;Lang Li ,&nbsp;Wenyan Zhao ,&nbsp;Wen Zeng","doi":"10.1016/j.biomaterials.2025.123936","DOIUrl":"10.1016/j.biomaterials.2025.123936","url":null,"abstract":"<div><div>In acute kidney injury (AKI), the loss of peritubular capillaries further aggravates the disease. Cell transplantation represents an innovative precision therapeutic strategy. However, the low survival rate of transplanted cells and the low therapeutic efficiency remain challenges for clinical application. Here, we constructed a Needlepatch loaded with the nanozymes GTFG@Fe₃O₄, and attached to a 3D printed patterned cell tubular networks hydrogel patch for <em>in situ</em> kidney transplantation. In the early stage of AKI, the nanozymes can effectively target ATG4B protein-enriched microenvironment, preventing the infiltration of the NLRP3 inflammasome and cellular damage, relieving inflammation. During the later stage, human induced pluripotent stem cells (hiPSCs) derived podocyte-attached patterned tubular networks of endothelial cells facilitated the rebuilding of renal microvascular network, promoting regeneration. In this process, the integration of the Needlepatch with host kidney is established. This engineered kidney composite patch alleviates the damage caused by AKI in a programmed manner and demonstrates considerable therapeutic potential in promoting renal microvascular reconstruction.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123936"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alkalinity and LSPR effect-based cuproptosis sensitizer to reverse tumor microenvironment for melanoma therapy","authors":"Lidan Liu ,&nbsp;Mei Li ,&nbsp;Panpan Huo ,&nbsp;Shun Xing ,&nbsp;Feng Peng ,&nbsp;Haifeng Zhang ,&nbsp;Haobo Pan ,&nbsp;Yuehua Li ,&nbsp;Xuanyong Liu","doi":"10.1016/j.biomaterials.2025.123913","DOIUrl":"10.1016/j.biomaterials.2025.123913","url":null,"abstract":"<div><div>Cuproptosis is a promising therapeutic strategy for tumor, but its therapeutic efficacy is limited by the weak acidity and high concentration of glutathione (GSH) in the tumor microenvironment (TME). In this study, a novel alkalinity and localized surface plasmon resonance (LSPR) effect-based nanoreactor (MgO/Cu@C) is constructed to sensitise cuproptosis. Firstly, the alkalinity produced by MgO could reverse the acidic tumor microenvironment. Additionally, near-infrared (NIR) induced photothermal property and LSPR effect synergistic alkalinity can enhance GSH depletion of MgO/Cu@C. Thus, MgO/Cu@C+NIR sensitizes melanoma cells to cuproptosis by reversing TME. Furthermore, RNA sequencing transcriptome analysis confirms that MgO/Cu@C+NIR induces cuproptosis through copper overload-triggered lipoylated protein aggregation, inhibition of tumor metabolic pathways by alkalinity, NIR-drived HSP hyperactivation that depletes ATP reserves, and phosphatidylinositol signaling-mediated hijacking of survival pathways, which synergistically enforces irreversible metabolic collapse for melanoma cells. Meanwhile, MgO/Cu@C+NIR could inhibit bacterial infection and promote wound healing, thus addressing dual clinical applications for melanoma treatment and wound healing. Particularly, this study firstly reveals the mechanisms by which alkalinity and LSPR effect potentiate GSH depletion, as well as that alkalinity could sensitise cuproptosis by reversing the acidic microenvironment of tumor. The study provides a promising perspective for potential melanoma treatment based on cuproptosis.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123913"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145838272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering bioactive fibrous constructs: Bioprinting stem cell-laden collagen-derived hydrogels with short collagen microfibers","authors":"Hongjuan Weng ,&nbsp;Monize C. Decarli ,&nbsp;Wen Chen ,&nbsp;Katrien V. Bernaerts ,&nbsp;Lorenzo Moroni","doi":"10.1016/j.biomaterials.2025.123965","DOIUrl":"10.1016/j.biomaterials.2025.123965","url":null,"abstract":"<div><div>Natural hydrogels (e.g., collagen hydrogels) show good potential in understanding cell-matrix interaction and find application in tissue engineering. However, it remains challenging to bioprint cell-laden natural hydrogels with good printability, shape retention and stability. In this study, non-water-soluble short collagen type I microfibers (COL-I μFiber) were blended with water-soluble methacrylated collagen peptide (COPMA) and xanthan gum (XG), forming an interpenetrated network, and bioprinted into stable natural-derived COPMA-μFiber-XG constructs, followed by <em>in situ</em> stem cell proliferation and differentiation. First, to enhance the printability and the mechanical properties of COPMA, a COPMA-μFiber-XG bioink was developed, featuring rapid UV-curing and self-healing properties. The encapsulated human mesenchymal stem cells (hMSCs) spread along the COL-I μFibers in the bioprinted constructs, with increased metabolic activity and production of extracellular matrix and bioactive proteins (COL-I and scleraxis) in 28 days. The internal biophysical and biochemical signals provided by COL-I μFibers and the fibrous COPMA matrix synergistically interacted with exogenous biochemical signals (e.g., transforming growth factor-beta 3) to further promote stem cell differentiation. Overall, bioprinted fibrous COPMA-μFiber-XG constructs are biocompatible and bioactive matrices to support hMSCs proliferation and differentiation.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123965"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide-conjugated biodegradable polyester scaffolds for bone regeneration","authors":"Tongqing Zhou ,&nbsp;Peter X. Ma","doi":"10.1016/j.biomaterials.2025.123919","DOIUrl":"10.1016/j.biomaterials.2025.123919","url":null,"abstract":"<div><div>Bone grafting remains one of the most common surgical procedures worldwide, with alloplastic grafts offering scalable and versatile alternatives to autografts. Biodegradable polyester-based scaffolds have emerged as a promising solution due to their tunable mechanical properties, biocompatibility, biodegradability, and recent advances in fabrication technologies. However, their lack of intrinsic bioactivity has driven increasing interest in bioactive functionalization. As a candidate for such functionalization, peptides offer several advantages, including ease of synthesis, specificity in biological interactions, and adaptability to chemical modification. This review provides a comprehensive overview of biodegradable polyester–peptide scaffold systems for bone tissue engineering. In particular, the review outlines essential design requirements for bone scaffolds, introduces widely used polyesters, and summarizes established techniques for scaffold fabrication and peptide conjugation. A range of examples demonstrating in vitro and in vivo efficacy is presented to depict the current progress in peptide-functionalized polyester scaffold systems. By summarizing current advances and outlining key challenges, this review inspires the rational design of next-generation scaffolds for bone regeneration.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123919"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145825496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic microenvironment-forming porous hydrogels for the protection of phenylalanine ammonia-lyase in the intestine","authors":"Sofie Dhondt ,&nbsp;Philippe Delbreil ,&nbsp;Shihao Pei ,&nbsp;Catherine Nadeau ,&nbsp;Inès Kadi ,&nbsp;Isabelle Masseau ,&nbsp;Fatma Moawad ,&nbsp;Xavier Banquy ,&nbsp;Davide Brambilla","doi":"10.1016/j.biomaterials.2025.123942","DOIUrl":"10.1016/j.biomaterials.2025.123942","url":null,"abstract":"<div><div>Biological therapeutics drive biomedical innovation, yet their oral delivery is hindered by gastrointestinal instability. Phenylalanine ammonia-lyase (PAL), a promising enzyme for phenylketonuria management, exemplifies this challenge. Here, we present ultraporous template-based hydrogels (TGels) that protect and deliver PAL in the small intestine. PAL-TGels are obtained via UV crosslinking of poly(ethylene glycol) diacrylamide in the presence of sacrificial CaCO₃ templates, followed by absorption-based loading of PAL and a protease inhibitor. The interconnected porous matrix retains PAL while allowing phenylalanine and <em>trans</em>-cinnamic acid diffusion for continuous catalysis. In vitro studies confirmed robust protein retention and preserved enzymatic activity in simulated intestinal fluid, without impairing global trypsin function, while large animal tests validated matrix properties and transit. This fabrication-efficient platform enables localized intestinal enzyme protection, offering a promising route toward safe and accessible oral PAL therapy for phenylketonuria.</div></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":"329 ","pages":"Article 123942"},"PeriodicalIF":12.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145831704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}