Spinal cord injury (SCI) is a highly disabling central nervous system disorder. Tissue engineering strategies utilizing multifunctional hydrogels for neural stem cell (NSC) delivery represent a promising therapeutic direction for SCI. Herein, a temporally responsive dual-targeting multifunctional hydrogel (EnpMG-bSH) for NSC delivery is reported. An artificial intelligence (AI)-assisted designed TGF-β-targeted lysosome-targeting chimera (LYTAC) peptide EndoP144 is released in a temporally controlled manner in response to the gradually elevated matrix metalloproteinase-2 (MMP-2) in the SCI lesion site, enabling precise transforming growth factor-β (TGF-β) regulation. Adhesive silk fibroin nanoparticles anchored with si- Notch1 -loaded hybrid exosomes are incorporated to induce neuronal differentiation of NSCs, support synaptic remodeling and exert concurrent immunomodulatory effects. This system attenuates glial scarring by downregulating the TGF-β signaling pathway in astrocytes, modulates the differentiation of NSCs via targeted modulation of the Notch1 pathway, and reshapes the local inflammatory microenvironment toward an anti-inflammatory phenotype, significantly improving locomotor and sensory recovery in SCI mice. Collectively, the AI-assisted EnpMG-bSH hydrogel-NSCs complementary therapeutic strategy provides a potential framework for coordinated local treatment of SCI.
Background/Aims Achieving functional cure (hepatitis B surface antigen [HBsAg] loss) and discontinuing lifelong nucleos(t)ide analog (NUCs) therapy are critical clinical goals in chronic hepatitis B (CHB) management. This study evaluated the long-term clinical outcomes and cost-effectiveness of different treatment strategies aimed at functional cure in hepatitis B e antigen (HBeAg)-negative patients with CHB across Asia-Pacific income strata. Methods A Markov state-transition model was developed to project 30-yr hepatitis B virus (HBV) disease outcomes in HBeAg-negative patients. Three finite strategies, PegIFN add-on to NUCs (PegIFN+NUC), switching from NUCs to PegIFN (Switch), and bepirovirsen add-on to NUCs (Bepi+NUC), were compared with lifelong NUC therapy. Analyses were stratified by country income level (high-income country [HIC], upper-middle-income country [UMIC], and lower-middle-income country [LMIC]). Costs were estimated from the health care payer perspective in 2023 USD. Incremental cost-effectiveness ratios (ICERs), probabilistic sensitivity analyses, and cost-effectiveness acceptability curves were generated across a range of willingness-to-pay thresholds. Results Switch led to the largest reduction in hepatocellular carcinoma (31%) and HBV-related deaths (32%). In HIC, Switch was the dominant strategy (lower cost and higher quality-adjusted life years [QALYs] than standard care). In UMIC and LMIC settings, Switch remained highly cost-effective with ICERs of 1774 and 2200 per QALY gained, respectively. Probabilistic sensitivity analysis demonstrated a >89% probability of finite PegIFN strategies being cost-effective at 1× GDP per capita thresholds across all income strata. In contrast, the bepirovirsen add-on strategy was dominated in all settings due to high acquisition costs and the impact of modeled seroreversion on long-term gains. Conclusions Finite PegIFN-based combination therapies are cost-effective toward functional cure in AP region. While bepirovirsen represents a major milestone in HBV drug development, its current economic viability is limited by high costs and durability concerns. Policy efforts should prioritize optimizing established immunomodulatory combinations to accelerate global hepatitis B elimination.
Toll-like receptor 7 (TLR7) is an endosomal sensor of single-stranded RNA that is highly expressed in macrophages and contributes to post-infarct inflammation. Whether TLR7 also restrains macrophage reparative function, particularly efferocytosis and clearance of inflammatory debris, remain unclear. Using a murine model of myocardial ischemia–reperfusion (I/R) injury, we showed that TLR7 deficiency mitigated inflammation, reduced infarct size and alleviated adverse ventricular remodeling. Beyond its anti-inflammatory effects, TLR7 deficiency reprogrammed macrophages toward a reparative phenotype, characterized by decreased pro-inflammatory cytokine production and increased expression of anti-inflammatory mediators, including IL-10 and TGF-β, consistent with M2-like polarization. Single-cell RNA sequencing revealed a subset-specific mechanism in which TLR7 deficiency suppressed inflammatory signaling in M1 macrophages while enhancing efferocytosis-related pathways in M2 macrophages. This was accompanied by upregulation of key phagocytic receptors and machinery, including CD36, LRP1, MerTK, AXL and Rac1, and functionally translated into enhanced efferocytic capacity and reduced apoptotic burden. Notably, TLR7 deficiency also promoted macrophage-mediated clearance of neutrophil extracellular traps (NETs) without affecting NETosis, identifying a previously unrecognized role for TLR7 in regulating NET resolution. Consistent with these findings, NET formation was observed following myocardial injury in both murine I/R models and patients undergoing percutaneous coronary intervention.In conclusion, our data identify TLR7 as a macrophage-intrinsic checkpoint that limits efferocytosis and NET disposal, thereby impairing inflammation resolution after myocardial injury. Targeting TLR7 may therefore represent a therapeutic strategy to suppress excessive inflammation while restoring pro-resolving macrophage functions and improving cardiac repair.
Fish-mediated allergic diseases are characterized by high prevalence, clinical severity, sensitization potential, and lifelong persistence. Their growing threat to public health has made them a major public health challenge requiring urgent attention. Due to species diversity resulting from evolutionary processes and processing methods, fish consumption patterns vary appreciably across global diets. The molecular structural and physicochemical variations and conservation among different allergens can induce distinct or cross-reactive immunological responses and clinical phenotypes in vivo, posing appreciable challenges to precise clinical diagnosis and personalized treatment. Deepening our understanding of the underlying mechanisms linking these structural characteristics and immune responses will help overcome current clinical difficulties, providing theoretical support and practical guidance for developing more effective allergy prevention and control strategies for the majority of patients. Recent studies indicate that fish allergies involve diverse species, with the structural characteristics and conserved nature of antigenic epitopes serving as the core molecular basis for mediating allergies and cross-reactions. Bioinformatics technologies have advanced the identification, analysis, and prediction of fish allergens and antigenic epitopes, providing theoretical support for elucidating sensitization mechanisms and the nature of cross-reactions. Diagnostic techniques have appreciably enhanced specificity and clinical value. Building upon this foundation, hypoallergenic technologies leverage high-temperature processing, enzymatic hydrolysis, fermentation, and other methods to selectively disrupt antigenic epitope structures or reduce allergen content, effectively diminishing their allergenicity. This approach has led to notable progress in the production of hypoallergenic aquatic products. This review focuses on elucidating the key structural and molecular characteristics of fish allergens, emphasizing the immunological mechanisms underlying allergic reactions and the nature of cross-reactivity. It comprehensively reviews the current status and advances in diagnostic and therapeutic technologies, summarizes the developmental trends in the field, and outlines future research directions. By continuously deepening scientific understanding of the biological properties of fish allergens, this work provides additional theoretical foundations and conceptual insights for developing more efficient and precise strategies for allergy prevention, control, and intervention.
