Gastrointestinal viruses such as rotavirus remain a major cause of childhood gastroenteritis and mortality worldwide. Although current live-attenuated rotavirus vaccines are effective, they face challenges including production, reduced efficacy in low- and middle-income countries, and rare adverse events, highlighting the need for vaccines that can induce strong gut mucosal immunity. Here, we introduce a lipid nanoparticle (LNP) platform that codelivers messenger RNA (mRNA) and the retinoic acid receptor agonist Am80 (Am80-LNP), enabling antigen-specific mucosal immune responses in the gut via parenteral intramuscular vaccination. Am80 incorporation preserved the vaccine's ability to imprint expression of the gut-homing receptors CCR9 and α4β7 on T and B cells, improved mRNA delivery, enhanced lymph node accumulation, and mitigated injection-site inflammation driven by the LNP. In mice and Bama miniature pigs, Am80-LNP induced antigen-specific serum antibody titers, cellular immune responses, and intestinal IgA production. Neonatal mice vaccinated with Am80-LNP exhibited reduced incidence and duration of diarrhea after live rotavirus challenge, whereas LNPs without Am80 conferred negligible protection. These findings highlight the importance of gut mucosal immunity in mediating protection against rotavirus and suggest that Am80-LNP may offer a versatile mRNA vaccine platform against gastrointestinal viruses.

Background Osteoporosis (OP) poses a significant and growing global health burden. Extracellular Vesicles (EVs), as pivotal mediators of intercellular communication, offer transformative potential for OP therapy. However, the rapid expansion of this interdisciplinary field has resulted in a fragmented knowledge structure. While existing reviews focus on specific molecular mechanisms, a macroscopic, quantitative analysis of the global research landscape—from biological fundamentals to bioengineering applications—is lacking. Objective This study aims to provide a comprehensive bibliometric mapping of EV research in OP (2013–2025), decoding the paradigm shift from mechanistic exploration to precision engineering and identifying emerging frontiers. Methods Based on 450 publications retrieved from the Web of Science Core Collection, a multi-algorithm approach integrating Bibliometrix, VOSviewer, and CiteSpace was employed. This allowed for the visualization of global collaboration networks, intellectual bases, and dynamic evolutionary trends. Results The field exhibited a distinct "S-shaped" growth curve, entering an exponential phase post-2021. Geopolitically, China dominated the landscape (79.3% of publications) and served as the indispensable global network hub (Betweenness Centrality = 1.00), despite a high degree of domestic research focus (Single-Country Publications: 93.6%). Intellectual progress has shifted from early-stage themes of "miRNA regulation" to a current "Med-Engineering-Biology" convergence. The most significant frontiers include: (1) The application of plant-derived EVs (e.g., yam nanovesicles) as novel therapeutic agents; (2) The development of smart biomaterials (e.g., hydrogels) for sustained delivery; and (3) The transition from natural carriers to engineered precision therapeutics for bone regeneration. Conclusion EV research in OP is evolving beyond cell biology into a multidisciplinary engineering science. Future breakthroughs hinge on overcoming translational bottlenecks—specifically standardization and targeting efficiency—through the continued integration of nanotechnology, materials science, and clinical medicine. Plain language summary Osteoporosis (OP) is a growing global health burden affecting hundreds of millions of people. Extracellular vesicles (EVs), acting as natural messengers between cells, have shown revolutionary potential in regulating bone metabolism and treating OP. To clarify the fragmented knowledge structure of this rapidly expanding field, we conducted a bibliometric analysis of 450 studies published between 2013 and 2025. Our analysis reveals a shift from "biological mechanism" to "bioengineering application." While early research focused on basic cellular signaling (e.g., miRNAs), the current frontier is defined by engineering strategies—specifically, the use of plant-derived EVs (e.g., from yams) and smart biomaterials (e.g., hydrogels) for targeted bone repair. Geopolitically, China dominates the research landscape (contributing 79.3% of publications) and serves as the global network hub; however, international collaboration remains limited. This study provides a roadmap for future research, highlighting that the clinical translation of EV-based therapies depends on standardizing isolation protocols and enhancing global interdisciplinary cooperation.

Hyperuricemia (HU), a common metabolic disorder, is characterized by elevated serum uric acid (sUA) levels. Uricase, an enzyme that degrades uric acid(UA) into allantoin, is absent in humans due to a nonsense mutation. Messenger RNA (mRNA)-based protein replacement therapy, known for its efficiency and transient expression, has garnered significant research attention. This study focuses on developing a mRNA therapy for HU using human ancestral uricase ANC19, delivered via lipid nanoparticles (LNPs). We prepared ANC19-LNPs, characterized their physicochemical properties, and evaluated their expression and function in Huh7 cells. Results indicate successful preparation and characterization of ANC19-mRNA, which localizes to peroxisomes and demonstrates UA degradation capability in vitro. Biodistribution was validated in Balb/c mice. Concurrently, a HU mouse model was successfully established using siRNA-mediated knockdown of Uricase-mRNA. In HU mouse models, ANC19-LNPs achieved a 75.63 % UA degradation rate. To validate these promising findings in a more clinically relevant species, the therapy was evaluated in cynomolgus monkeys, where it also showed a therapeutic effect, the area under the curve (AUC) of the concentration-time curve for ANC19-LNPs was 32.647 h*mu g/ mL compared to 67.074 h*mu g/mL for the negative control. Biochemical blood tests in cynomolgus monkeys confirmed the safety of ANC19-LNPs. In conclusion, we have successfully developed an effective mRNA-based protein replacement therapy for UA degradation, showing promising efficacy and safety in both in vitro and in vivo studies.

Traditional ring-opening metathesis polymerization (ROMP) reactions exhibit broad functional group compatibility and precise control over polymer architectures, albeit with non-biodegradable backbones. Recent progress has resulted in a series of biode-gradable ROMP products with diverse cleavable functional groups, yet the majority of the monomers display moderate to low ring strain, which restricts their living polymerization reactivity. In this study, a novel category of readily available 7-oxa-2,3-diazanorbornenes (ODAN) is presented, which exhibits the highest ring strain (22.8 kcal/mol) compared to existing degradable ROMP monomers. This trait endows ODAN with the ability to perform living polymerization reactions, generating narrowly dis-persed homopolymers, block copolymers, and statistical copolymers with various cyclic olefin comonomers, thereby enabling pre-cise control over distribution of the biodegradable functional groups. Additionally, the resultant polymers comprise directly con-nected allyl hemiaminal ether and urethane units, which are hydrolysable at controllable rates. Thus, these well-defined, structure-tunable, and backbone-biodegradable ROMP polymers are applied as nano-etching materials and biodegradable delivery carriers.

Activation of the stimulator of interferon genes (STING) pathway holds immense potential for cancer immunotherapy. However, clinical translation of STING agonists such as cyclic GMP-AMP (cGAMP) is hindered by their inherent instability and poor cellular uptake efficacy. Herein, we report an iron oxide nanoparticle (IONP)-based carrier for delivering cGAMP via coordination chemistry. The ribose, phosphate, and adenine on cGAMP were leveraged to directly bind IONP, resulting in cGAMP-functionalized IONPs (Fe-cGAMP). Such a design greatly improved the cellular uptake and STING activation efficacy of cGAMP. Beyond delivery, IONPs promoted reactive oxygen species (ROS) production and activated Toll-like receptors, leading to synergistic immune activation alongside cGAMP. Fe-cGAMP exhibited robust antitumor effects in multiple mouse tumor models. In combination with immune checkpoint inhibitors, Fe-cGAMP could induce complete tumor remission in over 50% of treated mice, and these mice also remain tumor-free upon a subsequent challenge, demonstrating strong and long-lasting antitumor immune responses.

Iron oxide nanoparticles (IONPs) have wide biomedical applications and are initially considered with minimal immunogenicity. Recent studies reveal that IONPs can activate the immune system through reactive oxygen species (ROS) or interferon regulatory factor (IRF) pathways. However, the exact mechanism remains unclear. To address this question, IONP-stemmed spherical nucleic acids (SNAs) coupled with immunostimulatory CpG strands, denoted as Fe-CpG, are synthesized to explore the immune activation mechanisms. It is shown that Fe-CpG efficiently entered cells and simultaneously activated TLR7, TLR8, and TLR9 within the endosome, triggering the downstream IRF5, IRF7, and NF-κB pathways, rather than engaging in the STING pathway. The IONP core of Fe-CpG is essential for the activation of TLR7- and TLR8-mediated pathways. When used as an adjuvant with a COVID-19 subunit vaccine, Fe-CpG outperforms both gold nanoparticle-based SNA and the clinically approved aluminum adjuvant. These results reveal how IONPs activate innate immune pathways and highlight the potential of Fe-CpG as a potent nano-adjuvant.

Inhaled delivery of messenger RNA (mRNA) using lipid nanoparticle (LNP) holds immense promise for treating pulmonary diseases or serving as a mucosal vaccine. However, the unsatisfactory delivery efficacy caused by the disintegration and aggregation of LNP during nebulization represents a major obstacle. To address this, we developed a charge-assisted stabilization (CAS) strategy aimed at inducing electrostatic repulsions among LNPs to enhance their colloidal stability. By optimizing the surface charges using a peptide-lipid conjugate, the leading CAS-LNP demonstrated exceptional stability during nebulization, resulting in efficient pulmonary mRNA delivery in mouse, dog, and pig. Inhaled CAS-LNP primarily transfect dendritic cells, triggering robust mucosal and systemic immune responses. We demonstrated the efficacy of inhaled CAS-LNP as a vaccine for SARS-CoV-2 Omicron variant and as a cancer vaccine to inhibit lung metastasis. Our findings illustrate the design principles of nebulized LNPs, paving the way of developing inhaled mRNA vaccines and therapeutics.

Colorectal cancer (CRC) ranks among the most prevalent cancers globally, demanding innovative therapeutic strategies. Immunotherapy, a promising avenue, employs cancer vaccines to activate the immune system against tumors. However, conventional approaches fall short of eliciting robust responses within the gastrointestinal (GI) tract, where CRC originates. Harnessing the potential of all-trans retinoic acid (ATRA) and cytosine-phosphorothioate-guanine (CpG), we developed layered nanoparticles using a layer-by-layer assembly method to co-deliver these agents. ATRA, crucial for gut immunity, was efficiently encapsulated alongside CpG within these nanoparticles. Administering these ATRA@CpG-NPs, combined with ovalbumin peptide (OVA), effectively inhibited orthotopic CRC growth in mice. Our approach leveraged the inherent benefits of ATRA and CpG, demonstrating superior efficacy in activating dendritic cells, imprinting T cells with gut-homing receptors, and inhibiting tumor growth. This mucosal adjuvant presents a promising strategy for CRC immunotherapy, showcasing the potential for targeting gut-associated immune responses in combating colorectal malignancies.

Messenger RNA (mRNA) cancer vaccines are a new class of immunotherapies that can activate the immune system to recognize and destroy cancer cells. However, their effectiveness in treating colorectal cancer located on the mucosal surface of the gut is limited due to the insufficient activation of mucosal immune response and inadequate infiltration of cytotoxic T cells into tumors. To address this issue, a new mRNA cancer vaccine is developed that can stimulate mucosal immune responses in the gut by co-delivering all-trans-retinoic acid (ATRA) and mRNA using lipid nanoparticle (LNP). The incorporation of ATRA has not only improved the mRNA transfection efficiency of LNP but also induced high expression of gut-homing receptors on vaccine-activated T cells. Additionally, the use of LNP improves the aqueous solubility of ATRA, eliminating the need for toxic solvents to administer ATRA. Upon intramuscular injections, ATRA-adjuvanted mRNA-LNP significantly increase the infiltration of antigen-specific, cytotoxic T cells in the lamina propria of the intestine, mesenteric lymph nodes, and orthotopic colorectal tumors, resulting in significantly improved tumor inhibition and prolonged animal survival compared to conventional mRNA-LNP without ATRA. Overall, this study provides a promising approach for improving the therapeutic efficacy of mRNA cancer vaccines against colorectal cancer.

Traditional ring-opening metathesis polymerization (ROMP) reactions exhibit broad functional group compatibility and precise control over polymer architectures, albeit with non-biodegradable backbones. Recent progress has resulted in a series of biode-gradable ROMP products with diverse cleavable functional groups, yet the majority of the monomers display moderate to low ring strain, which restricts their living polymerization reactivity. In this study, a novel category of readily available 7-oxa-2,3-diazanorbornenes (ODAN) is presented, which exhibits the highest ring strain (22.8 kcal/mol) compared to existing degradable ROMP monomers. This trait endows ODAN with the ability to perform living polymerization reactions, generating narrowly dis-persed homopolymers, block copolymers, and statistical copolymers with various cyclic olefin comonomers, thereby enabling pre-cise control over distribution of the biodegradable functional groups. Additionally, the resultant polymers comprise directly con-nected allyl hemiaminal ether and urethane units, which are hydrolysable at controllable rates. Thus, these well-defined, structure-tunable, and backbone-biodegradable ROMP polymers are applied as nano-etching materials and biodegradable delivery carriers.

De novo peptide design is a new frontier that has broad application potential in the biological and biomedical fields. Most existing models for de novo peptide design are largely based on sequence homology that can be restricted based on evolutionarily derived protein sequences and lack the physicochemical context essential in protein folding. Generative machine learning for de novo peptide design is a promising way to synthesize theoretical data that are based on, but unique from, the observable universe. In this study, we created and tested a custom peptide generative adversarial network intended to design peptide sequences that can fold into the β-hairpin secondary structure. This deep neural network model is designed to establish a preliminary foundation of the generative approach based on physicochemical and conformational properties of 20 canonical amino acids, for example, hydrophobicity and residue volume, using extant structure-specific sequence data from the PDB. The beta generative adversarial network model robustly distinguishes secondary structures of β hairpin from α helix and intrinsically disordered peptides with an accuracy of up to 96% and generates artificial β-hairpin peptide sequences with minimum sequence identities around 31% and 50% when compared against the current NCBI PDB and nonredundant databases, respectively. These results highlight the potential of generative models specifically anchored by physicochemical and conformational property features of amino acids to expand the sequence-to-structure landscape of proteins beyond evolutionary limits.

Shingles is caused by the reactivation of varicella zoster virus (VZV) and manifests as painful skin rashes. While the recombinant protein-based vaccine proves highly effective, it encounters supply chain challenges due to a shortage of the necessary adjuvant. Messenger RNA (mRNA)-based vaccines can be rapidly produced on a large scale, but their effectiveness relies on efficient delivery and sequence design. Here, an mRNA-based VZV vaccine using a synergistic lipid nanoparticle (Syn-LNP) containing two different ionizable lipids is developed. Syn-LNP shows superior mRNA expression compared to LNPs formulated with either type of ionizable lipid and to a commercialized LNP. After encapsulating VZV glycoprotein E (gE)-encoding mRNA, mgE@Syn-LNP induces robust humoral and cellular immune responses in two strains of mice. The magnitude of these responses is similar to that induced by adjuvanted recombinant gE proteins and significantly higher than that observed with live-attenuated VZV. mgE@Syn-LNP exhibits durable humoral responses for over 7 months without obvious adverse effects. In addition, mgE@Syn-LNP protects vaccinated guinea pigs against live VZV challenges. Preliminary studies on the mRNA antigen design reveal that the removal of glycosylation sites of gE greatly reduces its immune responses. Collectively, Syn-LNP encapsulating gE-encoded mRNA holds great promise as a shingles vaccine.

Pulmonary delivery of immune checkpoint inhibitors (ICIs) holds promise for increasing drug concentration in the lung and reducing off-target side effects compared to systemic administration. However, the development of an ideal carrier capable of efficiently encapsulating ICIs, maintaining stability during fabrication and nebulization, and facilitating transport through the mucus barrier remains a significant challenge. Herein, we developed such a carrier by synthesizing a responsive polyethylene glycol (PEG) nanogel through crosslinking fourarm PEG via copper-free click chemistry. This approach allows for the efficient in situ encapsulation of ICIs using biocompatible PEG, eliminating the need for potentially toxic catalysts or coupling reagents. The covalently crosslinked network ensures excellent colloidal stability of nanogel during nebulization. Importantly, the PEG nanogel greatly enhances the mucus penetration and lung accumulation of free ICIs. Upon reaching the tumors, the PEG nanogel undergoes dissolution triggered by the overexpressed matrix metalloproteinase-9, leading to the release of encapsulated ICIs. We demonstrated that pulmonary delivery of PEG nanogel greatly enhanced the therapeutic efficacy of ICIs and alleviated the potential toxicity associated with intravenously injected ICIs using a lung metastasis model in mice. Overall, this work presents a simple, safe, and effective PEG nanogel platform for the pulmonary delivery of ICIs.

Herein, we aimed to explore the polysaccharide material basis of Serratula chinensis and establish its beneficial effects against colitis. A neutral polysaccharide (SCP) was extracted from S. chinensis in high yield using hot water. The molecular weights were calculated by HPSEC as Mw = 2928 Da, Mn = 2634 Da, and Mw/Mn = 1.11. FT-IR and 1D/2D-NMR spectroscopic analyses confirmed that SCP was an inulin-type fructan with α-D-Glcp-(1 → [1)-β-D-Fruf-(2]17) linkages. Treatment with SCP (200 or 400 mg/kg) alleviated dextran sulfate sodium (DSS)-induced mouse colitis symptoms, including the loss of body weight, increase of disease activity index score, and shortening of colon length. Histopathological and immunofluorescence assessments revealed that SCP could reduce pathological damage to the colon, restore the number of goblet cells, increase the content of glycoproteins in goblet cells and mucins in crypts, and enhance the expression of tight junction proteins ZO-1 and occludin. In addition, metagenomic sequencing revealed that SCP could improve the dysbiosis of gut microbiomes and act on multiple microbial functions. Moreover, SCP treatment increased the content of colonic acetic acid and butanoic acid. Collectively, these results indicated that SCP could alleviate the DSS-induced colitis in mice through regulation of intestinal barrier and gut microbiota.

Traditional ring-opening metathesis polymerization (ROMP) reactions exhibit wide functional group compatibility and precise con-trol over polymer architectures, albeit with nondegradable backbones. Recent progress has resulted in a series of degradable ROMP products with diverse cleavable functional groups that are derived from the corresponding monomers. However, the major-ity of the monomers display moderate to low ring strain, which restricts their living polymerization reactivity. In this study, a novel category of readily available 7-oxa-2,3-diazanorbornenes (ODAN) is presented, which exhibits the highest ring-strain (22.8 kcal/mol) compared to existing degradable ROMP monomers. This trait endows ODAN with the ability to perform living polymer-ization reactions, generating narrowly dispersed homopolymers, block copolymers, and statistical copolymers with various cyclic olefin comonomers, thereby enabling precise control over the distribution of degradable functional groups. Additionally, the re-sultant polymers comprise directly connected allyl hemiaminal ether and urethane units, which are hydrolyzed at controllable rates. Thus, these well-defined, structure-tunable, and backbone-degradable ROMP polymers are successfully applied as nano-etching materials and biodegradable drug delivery vehicles.

Modified metabolites play significant roles in disease occurrence, progression and diagnosis. Sensitive and accurate analytical methods for the quantification of these metabolites are therefore of great importance. In this study, a liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous measurement of 13 pairs of prototypes and their modified forms covering nucleobases, nucleosides and amino acids. In order to improve the quantification sensitivity and accuracy, two structure analogs named N-dimethyl-amino naphthalene-1-sulfonyl chloride (Dns-Cl) and N-diethyl-amino naphthalene-1-sulfonyl chloride (Dens-Cl) were introduced for twins labeling derivatization. Dns-labeling was utilized to react with target analytes while the Dens-labeling of standard compounds provided one-to-one internal standards. With the introduce of naphthalene and easily ionizable moiety tertiary ammonium, chromatography retention and separation of these polar metabolites were notably improved on C18 columns and the detection sensitivity was increased up to 400 folds. The method is sensitive with the lower limit of quantification (LLOQ) values of 0.002-0.5 mu g/mL. Comparisons of the performance of twins labeling derivatization and traditional chemical isotope labeling (CIL) derivatization verified the ability of our method in the absolute quantification. The established method was applied to human lung adenocarcinoma cell line A549 and its cisplatin resistant derivative A549/DDP. Significant shifts in 12 metabolites as well as 9 modified-to-prototypical ratios in A549/DDP were observed, demonstrating the utility of our method and the potential role of modified metabolites in mediating anticancer drug resistance. The method can be easily extended to determine other types of modified metabolites in various biological matrices, which will greatly expand our knowledge on these metabolites. (C) 2021 Published by Elsevier B.V.

Infectious diseases are an increasing threat to global biosafety. Vaccination is the most effective and cost-efficient method for preventing and controlling infectious diseases. The development of new vaccines is inextricably linked to the advancement of materials that serve as essential components of vaccines, such as antigens, adjuvants, and their carriers. The physicochemical and biological properties of vaccines—such as the kinetics of antigen retention and presentation—are determined by the material compositions of vaccines and carriers, affecting the overall efficacy. The sustained release of antigens prolongs their retention time in germinal centers and improves humoral immune responses. Pulsatile release that imitates clinical dosing regimens can improve patient adherence to vaccination, affording increased vaccine coverage. Herein, we review progress of materials innovation on altering vaccine release kinetics, which affects the overall vaccine efficacy, safety, and compliance.

A palladium-catalyzed asymmetric C-C bond activation/carbonylation of cyclobutanones with CO has been developed. This reaction provided an efficient method for the synthesis of chiral indanones bearing a quaternary carbon stereocenter in good yields with an excellent enantiomeric ratio, exhibiting good functional group tolerance. Transformations of the products to chiral 3,4-dihydroquinolin-2(1H)-one and 1H-indene further demonstrated the versatility of this reaction.

Abstract Hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hibernation-like or torpor state in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in rodents. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly recuperated in the mice with knockout of PDXK in medial preoptic area (MPA). We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and both directly activate MPA neurons to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hibernation-like state in rodents.

In order to discover and develop the new RSK kinase inhibitor, 50 pyridyl biaryl derivatives were designed and synthesized with LJH685 as the lead compound and their anti-tumor ability was tested. The results showed that the ability of 7d compound to inhibit the phosphorylation of YB-1 was comparable to that of LJH685. Among them, after preliminary screening, compound 7d showed good activity in inhibiting cell proliferation. Therefore, we took 7d as an example and performed molecular docking analysis on it. Judging from the overlapping combination diagram with LJH685, the results have verified that compound 7d has a similar skeleton to LJH685 and has a similar docking effect with RSK. Therefore, compound 7d is in line with the RSK inhibitor we designed and could be developed to a promising anti-tumor drug in the future.