Huaqiong Li

Neonatal hypoxic‐ischemic brain damage (HIBD) represents a leading contributor to neonatal death and persistent neurological impairments, yet effective therapeutic options beyond hypothermia remain limited. Excessive reactive oxygen species (ROS) production and Toll‐like receptor (TLR)‐mediated neuroinflammation contribute to neuronal loss during hypoxic‐ischemic injury. Here, a ROS‐responsive antioxidant nanomicellar system (BGT@NPEP) based on an NPEP‐PEG‐PPG (NPEP) platform is reported for targeted delivery of the anti‐inflammatory coumarin bergapten (BGT) to ischemic neonatal brain tissue. The nanomicelles incorporate ROS‐cleavable boronate ester‐linked nordihydroguaiaretic acid, conferring intrinsic antioxidant activity and stimulus‐responsive drug release, while a neutral, size‐controlled shell facilitates accumulation in the ischemic hemisphere. The therapeutic efficacy of BGT@NPEP was systematically evaluated in vitro using oxygen‐glucose deprivation models and in vivo in neonatal HIBD models. Mechanistic investigations indicate that BGT@NPEP significantly reduced oxidative stress, enhanced glutathione peroxidase 1 (GPX1) activity, suppressed TLR‐driven inflammatory signaling, and modulated microglial polarization by inhibiting the M1 phenotype and promoting M2 phenotype transition. These effects collectively attenuated neuronal injury, reduced infarct volume, and improved neurological outcomes. Overall, this study demonstrates a dual‐action, ROS‐responsive nanotherapeutic strategy that integrates redox regulation with targeted anti‐inflammatory delivery, providing a promising minimally invasive approach for neuroprotection in neonatal HIBD.

In sepsis‐induced acute lung injury (ALI), mitochondrial DNA (mtDNA) released from damaged lung cells is recognized by the cytosolic DNA sensor cyclic GMP‐AMP synthase (cGAS), leading to aberrant activation of the stimulator of interferon genes (STING) pathway. This signaling cascade amplifies inflammation and oxidative stress, ultimately resulting in severe pulmonary dysfunction and high mortality. Here, we present a hydrogen‐bonded organic framework (HOF‐101)‐based delivery system for DNase I that enables enzymatic clearance of cytosolic DNA and targeted suppression of the cGAS‐STING pathway in ALI. Following efficient pulmonary delivery and macrophage internalization, this DNase I@HOF‐101 platform effectively clears intracellular mtDNA, thereby attenuating inflammatory responses and alleviating acute lung injury. Moreover, the system exhibits desirable biocompatibility, minimal cytotoxicity, and enhanced enzymatic stability, highlighting its potential as a nanotherapeutic strategy for cGAS‐STING‐mediated inflammatory diseases.

Diabetic wounds represent one of the most intractable complications of diabetes, arising from a highly complex and self-perpetuating pathological microenvironment. This milieu is characterized by chronic inflammation, oxidative stress, impaired angiogenesis, peripheral neuropathy, immune dysregulation, recurrent infection, and marked dysfunction of resident cells and the extracellular matrix (ECM). These intertwined abnormalities not only hinder wound closure but also significantly increase the risk of chronic infection, amputation, and disability, thereby imposing substantial clinical and socioeconomic burdens. Conventional therapies, which typically target isolated aspects of wound pathology, often fail to disrupt the vicious cycle of non-healing, underscoring the urgent need for integrated, multi-target therapeutic strategies. Chinese herbal medicine (CHM) encapsulates a holistic therapeutic paradigm that is intrinsically aligned with the multi-factorial nature of diabetic wound management. CHM offers a diverse array of bioactive ingredients, including polysaccharides, saponins, flavonoids, alkaloids, and phenolics, that collectively exert anti-inflammatory, antioxidant, pro-angiogenic, neuroprotective, immunomodulatory, antimicrobial, and pro-proliferative effects. Moreover, many of these ingredients exhibit pleiotropic effects, enabling concomitant modulation of multiple pathological pathways to address the inherent complexity of diabetic wounds. However, the clinical translation of raw CHM is frequently hindered by poor bioavailability and rapid degradation at the wound site. Recent advances in CHM-based innovative delivery platforms have provided a transformative framework to overcome these limitations. This review highlights the emergence of CHM-loaded hydrogels and CHM-derived plant exosome-like nanovesicles (PELNs) as next-generation interventions. CHM-loaded hydrogels act as biomimetic scaffolds that facilitate controlled release and adaptively respond to microenvironmental cues (e.g., pH and reactive oxygen species (ROS)). Simultaneously, CHM-derived exosome-like nanovesicles serve as natural, biocompatible nanocarriers that enhance cellular uptake and molecular signaling, promoting regenerative healing through intercellular communication pathways. In this review, we systematically summarize the pathological features of diabetic wounds and synthesize the modern pharmacological mechanisms of representative CHM ingredients. We further evaluate the synergistic integration of CHM with advanced biomaterials and nanotechnology, emphasizing their translational potential from preclinical models to clinical evidence. By bridging traditional wisdom with cutting-edge bioengineering, these platforms offer a robust evidence-based framework for the modernized management of diabetic wounds.

Chronic diabetic wounds require continuous modulation of the hyperglycemia‐induced pathological microenvironment. Although glucose‐responsive biomaterials show promise for diabetic wound treatment, intelligent wound management with tissue specificity and multifactorial repair capacity remains urgently needed. Here, we develop a tissue‐homologous, glucose‐responsive hydrogel based on epidermis‐derived keratin functionalized with phenylboronic acid (Keratin‐PBA), which is crosslinked with oxidized sodium alginate (OSA) to form a double‐network hydrogel (cOK) and integrated with bioactive nanomicelles for adaptive wound microenvironment regulation. Co‐assembled nanomicelles (OA‐PG NMs), composed of oleanolic acid (OA) and propyl gallate (PG), exhibit glucose‐triggered release and complementary bioactivities targeting oxidative stress, inflammation, macrophage polarization, angiogenesis, fibroblast behavior, antibacterial activity, and MMP regulation. Notably, OA promotes angiogenesis via the TGR5‐Akt‐eNOS‐NO signaling pathway. The resulting cOK@NM hydrogel enables spatiotemporally controlled nanomicelle release and significantly accelerates diabetic wound healing in vivo, as evidenced by rapid wound closure, enhanced M2 macrophage polarization, robust neovascularization, improved collagen remodeling, reduced AGEs, broad‐spectrum antibacterial effects against E. coli and S. aureus , and increased granulation tissue formation. This work presents a tissue‐homologous, intelligently adaptive platform integrating intrinsic regenerative bioactivity with glucose‐responsive therapeutic adaptability.

The abnormal microenvironment of chronic diabetic wounds leads to the disorder of the tissue repair process. Herein, based on the principles of click chemistry, a multifunctional rapid gelation hydrogel dressing (MSFP hydrogel) was designed for the treatment of diabetic wounds. The hydrogel was formed via thiol-ene click reaction between thiolated Pluronic F127 (F127SH) and maleimide-modified gelatin (GelatinMAL). This thiol-ene click reaction required no metal catalyst, exhibited good biocompatibility, and proceeded under mild conditions. The system incorporated antimicrobial component F127-acetylbromide (F127AcBr) and puerarin (PUE) and responded to overexpressed matrix metalloproteinase 9 (MMP-9) at wound sites, enabling controlled drug release. In vitro experiments demonstrated that the MSFP hydrogel effectively eliminated ROS; modulated macrophage polarization; promoted human umbilical vein endothelial cell proliferation, migration, and tube formation; and exhibited robust antibacterial activity against Staphylococcus aureus and Escherichia coli. In vivo diabetic mouse wound models confirmed that the MSFP hydrogel synergistically improved the wound microenvironment by establishing barrier protection, inhibiting bacterial growth, reducing inflammation, promoting M2 macrophage polarization, and enhancing vascularization. Collectively, this multifunctional hydrogel can promote diabetic wound healing through immunoregulation, angiogenesis, and antibacterial activity, presenting a promising therapeutic strategy for clinical application.

Allosteric modulation has emerged as a powerful strategy for achieving superior selectivity and safety in drug discovery and protein function regulation. Unlike highly conserved orthosteric sites, allosteric pockets are structurally diverse and less evolutionarily constrained, making them particularly suitable for modulation by designed miniproteins. Miniproteins can provide extended binding interfaces and high affinity for shallow, dynamic, or cryptic regulatory surfaces that are often inaccessible to small molecules. Recent advances in artificial intelligence (AI) are transforming this field through deep learning-based structure prediction and generative modeling. These AI-driven approaches enable the identification of allosteric hotspots, characterization of conformational ensembles, and de novo design of structured miniprotein binders. They are rapidly expanding the landscape for designing selective modulators across diverse allosteric targets, including GPCRs, receptor tyrosine kinases, nuclear receptors, ion channels, and other protein–protein interaction systems. This review summarizes state-of-the-art AI-driven computational methodologies for designing miniproteins as potential allosteric modulators and discusses their current challenges and future opportunities in allosteric drug discovery.

Ionic conductive organohydrogels have attracted significant attention in wearable sensing due to their transparency, conductivity, and flexibility. However, simultaneously achieving mechanical softness, high transparency, environmental stability, and excellent sensing performance remains a significant challenge. Herein, a binary‐network ionic organohydrogel was fabricated using acrylamide and polyvinyl alcohol within a water/glycerol solvent system to impart anti‐freezing properties. The resulting organohydrogel exhibits high transparency (>95%) and remarkable stretchability (>1400%). Notably, the hydrogel‐based sensor demonstrates high strain sensitivity, a broad sensing range (2%–500%), and outstanding stability and durability over 1000 cycles. It can effectively monitor human motion across various joints, such as the wrist, elbow, and knee. Moreover, the sensor maintains reliable performance at both low (–20°C) and high (60°C) temperatures, showcasing excellent anti‐freezing and anti‐drying capabilities. It also possesses notable thermal sensitivity across a wide temperature range. Leveraging its dual sensitivity to strain and temperature, machine learning‐assisted technology was employed to recognize different breathing patterns, achieving an average prediction accuracy of 98.4%. This work lays a foundation for comprehensive respiratory health monitoring and holds promise for applications in daily health management and clinical practice.

Decellularized tissues have attracted considerable attention in tissue engineering and regenerative medicine due to their diverse sources and excellent biocompatibility. However, current decellularization techniques often compromise the integrity of the extracellular matrix, leaving harmful chemical residues or inadequately removing immunogenic cellular components. Consequently, the biocompatibility and clinical efficacy of decellularized tissues are undermined. To address these issues, a novel decellularization technique employing an electrical field has been proposed. In the resulting decellularized tissue, the residual DNA concentration was measured at 27.44 ± 7.27 ng/mg, satisfying the evaluation criteria (<50 ng/mg) in a significantly shorter process compared to chemical/enzymatic decellularization (∼2 h vs. ∼15 h) and without the use of toxic reagents. The microstructure was better preserved in electrically decellularized skin than in chemically/enzymatically decellularized skin, maintaining an interconnected porous microstructure that facilitates neo-tissue ingrowth. Cytotoxicity assessments confirmed the non-cytotoxic nature of electrically decellularized fish skin, with a cell survival rate (115.84 ± 10.78%) higher than that of chemically/enzymatically decellularized and native skins (105.57 ± 3.43% and 118.69 ± 6.53%, respectively). The hemolysis rate of decellularized skin using electrical techniques was the lowest (0.35 ± 0.26%) compared to that of chemically/enzymatically decellularized and native skins (1.089 ± 0.03% and 1.11 ± 0.06%), indicating non-hemolytic material. Furthermore, subcutaneous implantation demonstrated that electrically decellularized skin did not elicit severe immune responses and exhibited faster tissue integration than chemically/enzymatically decellularized skin. Therefore, electrical decellularization effectively removes cellular components while preserving the natural architecture without the use of harmful reagents, establishing a secure foundation for extensive applications in tissue engineering and regenerative medicine using decellularized tissues in the future.

Allosteric modulation has emerged as a powerful strategy for achieving superior selectivity and safety in drug discovery and protein function regulation. Unlike highly conserved orthosteric sites, allosteric pockets are structurally diverse and less evolutionarily constrained, making them particularly amenable to be modulated by designed miniproteins. Miniproteins can provide extended binding interfaces and high affinity for shallow, dynamic, or cryptic regulatory surfaces that are often inaccessible to small molecules. Recent advances in artificial intelligence (AI) are transforming this field through deep learning–based structure prediction and generative modeling. These AI-driven approaches enable the identification of allosteric hotspots, characterization of conformational ensembles, and de novo} design of structured miniprotein binders. They are rapidly expanding the landscape of designing selective modulators across diverse allosteric targets, including GPCRs, receptor tyrosine kinases, nuclear receptors, ion channels, and protein–protein interfaces. This review summarizes state-of-the-art AI-driven computational methodologies for designing miniproteins as potential allosteric modulators and discusses their current challenges and future opportunities in allosteric drug discovery.

Implant-associated infections and inadequate osseointegration are major contributors to orthopedic implant failures. Although hydrothermally grown zinc oxide (ZnO) nanorods on titanium (Ti) implants enhance antibacterial activity, their aggressive degradation and uncontrolled Zn²⁺ leaching do not meet the requirements for bone implants and can damage the surrounding tissues. This study introduces a crystal-damage-free nanoengineering mechanism to enhance the stability of ZnO nanorods by utilizing a carbon nanolayer as a sacrificial template between the ZnO core and TiO₂. This mechanism induced the formation of a hybrid Zn₂TiO₄ heterostructure within the carbon layer at a low temperature of 500 °C by reducing the required activation energy. This carbon layer acts as a diffusion barrier, allowing the unilateral diffusion of ZnO into TiO₂ while preventing Ti diffusion into the ZnO core. The resulting ZnO@TiO₂-6 heterostructure controlled Zn²⁺ leaching and exhibited significant osteogenic activity of MC3T3-E1 cells and potent antibacterial efficacy against S. aureus and E. coli due to the differential landscape of osteoblasts and bacteria. In vivo studies further confirm that ZnO@TiO₂-6 heterostructure eradicated 90% of bacteria, alleviated inflammation, and enhanced biocompatibility. Unlike Ti implants, which lack antibacterial properties, and ZnO alone, which induces inflammation, ZnO@TiO₂-6 nanorods provide enhanced stability, sustained Zn²⁺ release, optimized ROS levels, and dual antibacterial and osteogenic functions, making them a promising advancement for orthopedic and dental implants.