Spinal cord injury (SCI) creates a hostile microenvironment that severely limits neural regeneration and functional recovery. Although bioelectrical modulation has emerged as a promising strategy for SCI repair, existing biomaterials generally provide either passive electrical conduction or stimulus-responsive electrical generation, but rarely integrate both properties within a mechanically compliant scaffold suitable for spinal cord repair. Here, we developed an injectable, remotely activatable electroactive hydrogel (SMT) by integrating conductive MXene nanosheets into a silk fibroin/tannic acid matrix, endowing the scaffold with tissue-matched mechanics, continuous electrical conductivity, and stimulus-responsive electrical output. Upon ultrasound activation, SMT generated localized bioelectrical cues within the lesion site. At the cellular level, SMT exhibited intrinsic antioxidant and anti-inflammatory effects that were further enhanced by ultrasound activation, while SMT + US promoted autophagic flux through Ca[2+]-dependent JNK signaling. In a rat model of SCI, the ultrasound-activated hydrogel promoted neural tissue repair and remyelination, attenuated reactive gliosis, and improved functional recovery. Collectively, this study presents a remotely activatable electroactive hydrogel for SCI repair and provides a promising strategy for dynamic bioelectrical regulation during SCI repair.

Iron-driven reactive oxygen species (ROS) amplification forms a self-sustaining pathological cycle in Parkinson's disease (PD), yet remains difficult to therapeutically interrupt due to the lack of strategies that coordinate metal homeostasis and redox regulation. Here, we report an electronic-structure-engineered nanoregulatory strategy that regulates the iron-ROS cycle rather than passively scavenging ROS. Nitrogen-doped, herbal-derived carbon dots (CD) were rationally constructed to establish a conjugated electronic framework, in which heteroatom-induced electron delocalization defined redox-active sites and governed the coupling between iron chelation and catalytic ROS regulation. This structure-electronic state-function relationship enabled programmable disruption of the iron-ROS feedback loop at its source. Functionally, the nanoregulators achieved low-density lipoprotein receptor-related protein 1 (LRP1)-mediated brain delivery, exhibited efficient central nervous system exposure, and underwent brain clearance via the cerebrospinal fluid pathway. At the cellular level, they restored mitochondrial function, suppressed ferroptosis-associated lipid peroxidation, and reprogramed stress-related pathways toward neuronal survival. Transcriptomic analysis further revealed coordinated regulation of redox, metabolic, and inflammatory networks. In Parkinsonian mice, this strategy reduced iron deposition, preserved dopaminergic neurons, and improved motor function. Integration with levodopa further enabled sustained, disease-modifying neuroprotection.

Mesenchymal stem cell-derived extracellular vesicles are promising for treating pulmonary fibrosis. However, the generation of extracellular vesicles (EVs) bearing potent, specific therapeutic cargo remains a significant clinical challenge. This study aims to demonstrate how a material-instructive strategy can be utilized to engineer cargo-specific EVs by precisely mimicking the physiological breathing motion of the lung microenvironment. A dynamic culture system was developed by combining a photo-crosslinkable lung decellularized extracellular matrix with an auxetic scaffold. Mesenchymal stem cells (MSCs) were cultured on these scaffolds under dynamic stretching. The dynamically conditioned EVs (dEVs) were then collected, and their therapeutic mechanisms and efficacy were evaluated both in vitro and in vivo using bleomycin-treated human pulmonary fibroblasts and a bleomycin-induced rat pulmonary fibrosis model, respectively. Dynamic stretching on auxetic scaffolds enhanced MSC mechanotransduction, as indicated by the upregulation and nuclear accumulation of YAP. This mechanical activation drove a YAP-dependent biogenesis pathway, leading to the selective enrichment of miR-30 in dEVs. In vivo administration of dEVs effectively restored lung architecture and attenuated collagen deposition. Mechanistically, dEV-derived miR-30 exerted dual therapeutic effects by directly inhibiting myofibroblast activation and promoting the macrophage phenotype switch from pro-inflammatory M1 to anti-inflammatory M2. Furthermore, the EVs successfully restored mitochondrial homeostasis in damaged cells, thereby supporting tissue repair. EVs engineered with miR-30 mimics fully recapitulated the potent therapeutic effects of dEVs, significantly outperforming miR-100. This study successfully established an auxetic dECM scaffold-based mechanogenetic platform to engineer cargo-specific EVs. The findings indicate that mechanical priming optimizes EV therapeutic efficacy, highlighting the YAP/miR-30 axis and mitochondrial restoration as key targets for alleviating pulmonary fibrosis.

Traditional biomaterials commonly trigger a foreign body reaction after implantation, leading to fibrous encapsulation and poor osseointegration. Advances in osteoimmunology have enabled contemporary tissue engineering to redefine biomaterials as active modulators of the osteoimmune microenvironment rather than as passive scaffolds. At the core of this reconceptualization is the targeted control of macrophage polarization to establish an immune environment conducive to bone repair. The plasticity of macrophages reflects the dynamic balance between the M1 pro-inflammatory and M2 pro-regenerative states; this plasticity ultimately determines regenerative outcomes. This review offers a conceptual four-dimensional regulatory framework that extends from extracellular interface sensing to intracellular genome remodeling and progresses from material properties and signaling cascade stratification to mitochondrial reprogramming and non-coding RNA (ncRNA) networks. Within this framework, material interfaces function as platforms for activating, transducing, and integrating bioactive signals. These signals can be externally modulated to reshape intracellular metabolic organization and sustain mitochondrial function. At a finer regulatory tier, ncRNAs modulate signaling pathways to achieve the precise post-transcriptional regulation of gene expression. Central to this model is a bidirectional, spatiotemporally dynamic feedback loop linking intrinsic cellular machinery with extrinsic material systems. Linking material design parameters to dynamic biological responses lays a conceptual foundation for the development of biomaterials capable of the adaptive and programmable regulation of the osteoimmune microenvironment. Future research may focus on the precise temporal control of M1/M2 phenotypic switching and the coordinated presentation of multiple signals, thereby advancing the development of next-generation immunomodulatory biomaterials for bone repair.

Targeted protein degradation (TPD) has emerged as a powerful strategy for eliminating disease-driving proteins, yet its broader application remains constrained by limited target specificity and the lack of integrated therapeutic delivery functions. Here, we report Tri@N, a multimodal polymeric nanoplatform that extends hydrophobic polymer-based TPD to membrane-associated targets while simultaneously enabling immunomodulatory drug delivery. Tri@N is engineered to remain stable during systemic circulation but undergo intracellular disassembly in response to elevated GSH levels. This disassembly exposes hydrophobic polymer segments that function as a hydrophobic polymer tag, promoting EGFR destabilization and degradation through both proteasomal and autophagy-lysosomal pathways. In parallel, Tri@N releases niclosamide (NIC), which suppresses the STAT3/PD-L1 signaling axis. In colorectal cancer models, Tri@N achieved coordinated EGFR degradation and PD-L1 downregulation, resulting in enhanced CD8[+] T cell-mediated antitumor immunity and robust tumor suppression in vivo. These findings establish Tri@N as a dual-functional polymeric nanoplatform that integrates hydrophobic polymer tagging-mediated degradation of a membrane protein with therapeutic payload delivery, providing a versatile strategy for multimodal cancer therapy.

The repair and functional reconstruction of large segmental bone defects in load-bearing regions are extremely difficult, mainly because the body's capacity to recruit endogenous functional ions such as Ca[2+], Cu[2+], and Mg[2+] to facilitate mineralization and vascularization is compromised. Herein, inspired by the bioelectric field-mediated ion regulation in native bone, a biomimetic carbon fiber reinforced polyetherketoneketone (CF/PEEK) scaffold incorporated with a bio-heterojunction was fabricated via 3D printing, liquid-phase chemistry and hydrothermal treatment. The heterojunction composed of 2D nano-MXene and in-situ ZnS quantum dots enriches functional ions on the scaffold surface through an endogenous electric field, thereby remarkably improving its bioactivity. In vitro cell experiments demonstrated that the CF/PEEK biomimetic scaffold promotes cells' osteogenic and angiogenic differentiation through the epidermal growth factor receptor (EGFR)-mediated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. In vivo investigations via non-load-bearing lacunar and load-bearing segmental bone defect models verified that the CF/PEEK biomimetic scaffold possesses superior bone and vascular regeneration capacity, enabling rapid vascularized bone regeneration under complex stress conditions through a bone-vessel coupling mechanism. This work offers a novel strategy for repairing load-bearing large segmental bone defects and new insights into designing bioelectric field-guided biomimetic materials.

Overcoming premature activation of aggregation-induced emission photosensitizers (AIE-PSs) before they reach the tumor is critical for the broad clinical application of photodynamic therapy (PDT). Here, we report a bowl-shaped nanoplatform as a universal AIE delivery vessel, together with a new endoplasmic reticulum (ER)-targeting AIE PS (TSQE), for precision PDT. A hollow polydopamine (PDA) nanobowl was fabricated to confine oleic acid (OA) molecules within its cavity, forming a localized hydrophobic phase that attracts and disperses TSQE molecules into dynamic aggregates, thereby enabling efficient delivery while avoiding premature activation. The TSQE-OA mixture responds to pH stimuli in the tumor microenvironment, resulting in specific TSQE accumulation in the ER of tumor cells. Additionally, upconversion nanoparticles (UCNPs) co-loaded in the nanobowl enable deep-tissue activation of the TSQE molecules using 980 nm light, triggering potent apoptosis and ferroptosis via ER stress and lipid peroxidation (LPO). The therapeutic effect is further amplified by manganese deposited on the PDA shell, which catalyzes reactive oxygen species (ROS) generation in combination with the PDA's photothermal effect under 808 nm irradiation. In vitro and in vivo studies demonstrate superior and specific anti-tumor efficacy. Our nanobowl-based delivery platform and the TSQE represent a dual-level strategy for improving PDT precision.

The localized delivery of RNA therapeutics to mineralized tissue interfaces is limited by poor retention and rapid clearance at the target site. We report the development of a solid-phase transfection platform that functionalizes mineralized surfaces into bioactive nucleic acid reservoirs. Through the rational design and screening of a library of 21 piperazine-linked bisphosphonate ionizable lipids, we identified a lead formulation of bisphosphonate lipid nanoparticle (BP-LNP) that maximizes hydroxyapatite affinity without compromising transfection potency. Upon adsorption onto mineral substrates, these BP-LNPs resisted fluid removal and maintained surface-mediated, sustained delivery of encapsulated RNA cargo to adjacent cells. We demonstrated the versatility of this Mineralized Tissue-Targeting Expression System (MiTEX) composed of BP-LNPs in two therapeutic contexts: Cre recombinase mRNA-functionalized allogeneic bone grafts to genetically label de novo bone formation in vivo, and STAT3 siRNA delivery to reduce inflammation in human gingival explants. This platform provides a universal strategy for transforming inert calcium phosphate materials and tissues into locally bioactive RNA delivery systems for regenerative and immunomodulatory applications.

The regeneration of the dentin-pulp complex remains a critical challenge in oral regenerative medicine. Osteogenic growth peptide (OGP) has garnered significant attention due to its theoretical ability to promote the differentiation of human dental pulp stem cells (hDPSCs). However, its clinical potential is limited by rapid diffusion and susceptibility to enzymatic degradation within the tissue microenvironment. Inspired by the natural OGP-OGP binding protein (OGPBP) system, this study reports an OGPBP complex-mimicking peptide hydrogel (Gel Nap-OGP) for dental pulp regeneration. Gel Nap-OGP is obtained via ultraviolet-triggered co-assembly of two rationally designed peptides: an OGP mimetic peptide Nap-Phe-Phe-Glu-Tyr-Gly-Phe-Gly-Gly-OH (NapFFEOGP(10-14)) and an OGPBP mimetic peptide Nap-Phe-Phe-Glu-Lys(acrylamide)-Lys(acrylamide)-OH (NapFFEK(aa)K(aa)). The resulting hydrogel nanofiber network loads NapFFEOGP(10-14) through dynamic non-covalent interactions, effectively preventing the peptide from enzymatic degradation and facilitating its controlled release. In vitro studies demonstrate that Gel Nap-OGP maintained favorable cytocompatibility without significantly affecting hDPSC proliferation, while enhancing osteogenic/odontogenic differentiation, as indicated by increased expression of RUNX2, ALP, and DSPP. Furthermore, in vivo experiments confirm its excellent biosafety, along with its ability to enhance mineralized tissue formation in an ectopic renal capsule model. RNA sequencing analyses further reveal that Gel Nap-OGP can modulate gene expression programs related to classical osteogenic/odontogenic signaling pathways. We anticipate that this biomimetic peptide hydrogel could be applied for dental pulp regeneration in clinical settings in the future.

Conventional surgery for locally advanced rectal cancer (LARC) faces challenges including difficult sphincter preservation and high recurrence rates. Neoadjuvant immunotherapy holds promise for addressing this clinical challenge by reducing the preoperative tumor burden and activating immune memory. However, the benefit remains limited for most patients, who present with the pMMR/MSS subtype, a so-called "immunosuppressive tumor". Therefore, we developed an injectable thermosensitive hydrogel (OXA/αCD47/CpG@PLEL) that, upon transanal minimally invasive injection, achieves precise location and in situ sustained release of oxaliplatin (OXA), anti-CD47 antibody (αCD47), and CpG oligodeoxynucleotides (CpG) at the tumor site for neoadjuvant immunotherapy of LARC. Released OXA induced cancer cell immunogenic cell death, accompanied by exposure of the calreticulin "eat me" signal to macrophages, while αCD47 blocked the CD47-SIRPα "don't eat me" pathway between cancer cells and macrophages, and CpG further activated macrophages. These effects synergistically enhanced phagocytosis by macrophages, while the combination of αCD47 and CpG promoted M1-type polarization of macrophages. In an orthotopic mid-low LARC mouse model, a single preoperative dose of this hydrogel effectively enhanced macrophage antitumor activity. In addition, it promoted dendritic cell maturation and the subsequent systemic CD8[+] T-cell response. This triple-action approach significantly reduced the tumor burden and in turn facilitated surgical resection, minimized organ damage, and suppressed postoperative recurrence, culminating in markedly prolonged survival. More importantly, tumor-free mice after initial treatment resisted tumor re-exposure, which was accompanied by increased effector memory T cells. This injectable thermosensitive hydrogel with multipathway macrophage immunomodulation may enhance innate and adaptive immune responses through minimally invasive intervention, precise drug delivery, and long-term regulation, representing a potential synergistic neoadjuvant immunotherapy strategy for LARC.

Inflammatory bowel disease (IBD), encompassing chronic relapsing gastrointestinal disorders, remains a profound clinical challenge because conventional therapeutics are often impeded by systemic off-target toxicities and suboptimal retention at inflamed mucosal sites. Herein, an inflammation-activated and retentive injectable hydrogel is presented, which leverages pathological nitric oxide (NO) overproduction as both a therapeutic target and an autonomous release trigger. An NO-responsive and NO-scavenging polymer (NRSP) incorporating an NO-cleavable o-phenylenediamine (o-PD) motif is formulated into cationic, dexamethasone-encapsulating micelles and electrostatically assembled with anionic hyaluronic acid (HA) to form a shear-thinning hydrogel that facilitates minimally invasive rectal administration and ensures prolonged, localized retention at the inflamed mucosal interface. Upon exposure to the NO-rich inflammatory microenvironment, structural disruption of NO-responsive and NO-scavenging micelles (NRSM) compromises the electrostatic integrity of the HA-micelle network, thereby reducing the storage modulus and accelerating cargo release. In vitro evaluations using lipopolysaccharide-stimulated macrophages demonstrate that NRSM hydrogels effectively reduce intracellular and extracellular NO levels and attenuate pro-inflammatory cytokine secretion. Furthermore, the HA matrix mediates disease-adaptive localization through CD44 receptor recognition and preferential electrostatic adhesion to positively charged inflammatory interfaces, resulting in enhanced colonic retention in DSS-induced colitis models ex vivo. Following rectal administration in DSS-induced mice, NRSM-based hydrogels significantly alleviate disease severity, reduce colonic NO and inflammatory cytokine levels, and rescue mucosal architecture and mucin-associated features. Notably, dexamethasone-loaded NRSM hydrogel exerted the most potent synergistic therapeutic benefit. Overall, this disease-responsive hydrogel platform establishes an effective localized intervention for IBD, merging intrinsic pathological NO scavenging with controlled drug delivery.

Subtherapeutic microwave heating at tumor margins, arising from the need to balance therapeutic efficacy with clinical safety during microwave ablation, represents a major cause of postoperative tumor recurrence. Therefore, developing biomaterials that combine strong microwave susceptibility with immunostimulatory activity is of practical significance for enhancing the therapeutic impact of current microwave ablation techniques on tumor rim cells. In this study, we prepared an injectable calcium peroxide nanoparticle-embedded alginate hydrogel (CaO2-ALGel) to synergistically sensitize cancer cells to microwave hyperthermia. Upon decomposition in response to tumor acidity, CaO2 enhances microwave heating through ion confinement effects and synergizes with subtherapeutic microwave heating to broadly induce necroptosis in cancer cells via activation of the phosphorylated receptor-interacting protein kinase 3 and phosphorylated mixed lineage kinase domain-like signaling pathways. Following locoregional administration, CaO2-ALGel with its superior tumor acidity-neutralizing ability synergized with subtherapeutic microwave hyperthermia to elicit potent therapeutic and protective antitumor immunity, effectively suppressing both primary and rechallenged tumors. Moreover, CaO2-ALGel-assisted microwave hyperthermia inhibited systemic tumor metastasis, particularly when combined with immune checkpoint blockade therapy in an orthotopic murine model of triple-negative breast cancer. This study underscores the dual capacity of CaO2-ALGel to enhance microwave ablation by simultaneously improving microwave heating efficacy and promoting immunogenicity.

Severe bacterial enteritis causes significant clinical manifestations and has a widespread impact, while conventional antibiotic treatments have exacerbated antimicrobial resistance, underscoring the urgent need for effective therapeutic alternatives. To address this critical gap, we develop a biohybrid therapeutic platform that combines antibacterial ergothioneine-capped gold nanoclusters (EGT-Au NCs) with Spirulina for oral delivery. EGT alone has no antibacterial activity, yet the engineered EGT-Au NCs exhibit antibacterial efficacy approaching that of conventional antibiotics, while also minimizing the risk of resistance. Beyond their potent antibacterial activity, EGT-Au NCs display exceptional biocompatibility, negligible hemolytic toxicity, enhanced anti-inflammatory and antioxidant properties that collectively promote host recovery. By harnessing the natural gastrointestinal adhesion and prolonged retention of Spirulina (EGT-Au NCs@SP), this system enhances localized antimicrobial efficacy. In vivo studies confirm the EGT-Au NCs@SP platform exhibits robust antibacterial performance, effective inflammation suppression, and enhanced intestinal repair in Salmonella Typhimurium infection models. Mechanistic investigations demonstrate that EGT-Au NCs exert a sophisticated antibacterial mechanism, actively disarming bacteria by impairing flagellar assembly, disrupting biofilm formation, attenuating bacterial virulence, and significantly reducing epithelial invasion. Notably, Salmonella Typhimurium strains that acquired resistance to conventional antibiotics remainsensitive to EGT-Au NCs. This multifunctional biohybrid nanoplatform represents a safe and effective oral therapeutic strategy, offering a promising alternative to antibiotics for combating gastrointestinal infections and antimicrobial resistance.

Live biotherapeutic products (LBP) hold great promise for the treatment of intestinal diseases such as inflammatory bowel disease and colorectal cancer, owing to their unique abilities to modulate the gut microbiota, regulate host immunity, and influence drug metabolism. However, the use of natural strains remains constrained by several challenges, including poor survival, limited colonization efficiency, immune clearance and non-specific targeting. Rational engineering of bacteria can overcome these limitations, while biomaterials, owing to their safety and versatile functionalities, provide powerful tools for bacterial modification. Recent studies have focused on developing biomaterial-modified bacteria (BMB) using lipid-based coatings, hydrogels, organic-inorganic hybrid materials, antibody or functional protein and cell membrane. This review systematically summarizes strategies for modifying bacterial surfaces with these biomaterials, elucidates the underlying mechanisms by which they enhance bacterial performance, and highlights recent advances in this field, offering insights that may inspire the design of the next generation of BMB based on high-throughput platforms, synthetic biology, and artificial intelligence (AI).

Scaffold-guided bone regeneration (SGBR) is an emerging strategy for reconstructing large segmental bone defects, but the biological basis and conditions of its clinical performance remain incompletely defined. In this narrative review, we consolidate a mechanobiological framework that conceptualizes SGBR as the spatiotemporal compartmentalization of the bone-healing cascade, whereby temporary architectures may organize a large defect into multiple, communicating, graft-loaded mechano-transport compartments. Within this nested scaffold-graft-host-fixation system, these compartments are defined by their local mechanical environment, transport properties, and evolving biological composition, which together influence hematoma organization, immune and vascular responses, graft incorporation, osteogenesis, and remodeling. We synthesize fracture and nonunion biology, the diamond concept, interfragmentary-motion theory, scaffold architecture studies, preclinical defect models, and heterogeneous early clinical evidence. Because current clinical evidence consists mainly of case reports and small heterogeneous case series, we interpret these data as feasibility signals. By integrating established mechanisms spatially and temporally, the framework proposes the evolving graft-loaded repair compartment as the mesoscale functional unit of SGBR and yields testable biomaterials design propositions. It proposes that durable regeneration depends on both stage-appropriate local compartment competence and progressive continuity between compartments; accordingly, pore architecture, graft distribution, graft-loaded permeability, surface bioactivity, degradation, wet-state mechanics, and fixation coupling should be evaluated as interacting variables under clinically relevant conditions. Finally, we map these variables to healing stages and technological readiness, identify evidence gaps, and define validation requirements for the implanted patient-specific scaffold-graft construct.