To address monotherapy limitations in oncology, synergistic strategies are urgently needed to circumvent drug resistance and achieve favorable therapeutic outcomes. The development of new nanoformulations has emerged as one of the most promising approaches to resolve these challenges. In this study, we engineered an iRGD peptide-functionalized Fe single-atom nanozyme (FeSAN@iRGD) that integrates dual therapeutic modalities. The FeSAN@iRGD demonstrates exceptional peroxidase-like catalytic activity and achieves a remarkable 29.5% photothermal conversion efficiency under 808 nm laser irradiation, enabling effective synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT). Density functional theory calculations reveal that the atomically dispersed Fe-N4 active sites facilitate efficient catalytic conversion of endogenous H2O2 into highly cytotoxic hydroxyl radicals in tumor microenvironment. The surface-conjugated iRGD peptide significantly enhances tumor-targeted accumulation. Both in vitro and in vivo evaluations confirm that the combined CDT/PTT approach synergistically enhances tumor cell apoptosis and suppresses tumor growth. Proteomic analysis comprehensively revealed reactive oxygen species (ROS)-mediated pathways including response to ROS, apoptosis, metabolic reprogramming, and cell cycle. This multifunctional nanozyme provides a promising paradigm for overcoming the therapeutic limitations of conventional cancer treatments through rational integration of catalytic nanomedicine and tumor-targeting strategies.

OSW-1, a steroidal disaccharide isolated from the bulbs of Ornithogalum saundersiae, has been extensively studied for its extremely potent cytotoxicity against the National Cancer Institute's 60 cancer cell lines with an average IC50 of 0.78 nM, while exhibiting selectivity toward normal cells. Although OSBP and ORP4L have been identified as its binding targets, their known functions appear insufficient to account for the compound's exceptional potency, suggesting the involvement of additional mechanisms and targets. Therefore, elucidating novel target proteins associated with its activity is essential for the further development of this molecule. Here, we disclose that OSW-1 can block the glycolytic pathway and trigger compensatory mitochondrial oxidative phosphorylation. This previously uncharacterized mechanism is relevant to the key rate-limiting enzyme, enolase 1 (ENO1), which shows subnanomolar affinity with OSW-1. Our study repurposes OSW-1 to be a small-molecule probe to investigate the function of ENO1 and a promising candidate for metabolism-targeted anticancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) exhibits pronounced desmoplasia, primarily attributed to the activation of pancreatic stellate cells (PSCs) from a quiescent state (quiescent PSCs [qPSCs]) to an activated form (activated PSCs [aPSCs]), which facilitates tumor progression and therapeutic resistance. This study investigates the potential of the vitamin D3 (VD) analog calcipotriol (Cal) to modulate this activation process and its impact on PDAC cell malignancy, with a particular focus on the thrombospondin 1/cluster of differentiation 47 (THBS1/CD47) signaling axis. Through analyzing VDR mRNA expression in aPSCs versus PDAC cells, we found that aPSCs are more responsive to VD signaling. Treatment with Cal significantly reduced aPSC activation, as evidenced by decreased α-SMA expression and THBS1 secretion, thereby diminishing stromal support for PDAC cell proliferation, migration, and invasion. These changes were mediated by the inhibition of the THBS1/CD47 axis, highlighting a novel mechanism by which Cal disrupts the supportive tumor microenvironment. Our findings highlight the therapeutic potential of targeting aPSCs with VD analogs in PDAC, suggesting a new direction for treatments that aim to interrupt the desmoplastic reaction and thereby inhibit PDAC progression.

Alopecia is a common disorder characterized by dysregulation of the hair follicle (HF) growth cycle, particularly the impaired activation of telogen follicles into a new anagen stage. Bone morphogenetic protein 2 (BMP2) acts as a critical inhibitory regulator that maintains hair follicle quiescence during early telogen, and its downregulation is closely associated with the telogen-to-anagen transition. Here, we designed and screened a series of siRNAs specifically targeting BMP2 and identified a human-mouse homologous siRNA candidate siBMP2-13. The chemically modified candidate (siBMP2-13-C) exhibited strong gene-silencing activity in HSF cells (IC50 = 0.20 nM). In early telogen mice, intradermal administration of the cholesterol-conjugated candidate (Chol-siBMP2-13-C) effectively reduced BMP2 expression in skin tissues, activated hair follicle stem cells, accelerated anagen onset, and enhanced hair regrowth. These findings support BMP2-targeting siRNA as a promising RNA interference-based strategy for the telogen to anagen transition and hair regrowth.

TXNIP and DYRK1A are two novel drug targets for the treatment of type 2 diabetes (T2DM), and their respective inhibitors have been shown to suppress islet β-cell apoptosis and promote islet β-cell proliferation. The quinazoline scaffold constitutes the core pharmacophore of TXNIP inhibitors. Harmine, a prototypical DYRK1A inhibitor bearing a β-carboline scaffold, has demonstrated robust β-cell proliferative activity. Carbazole serves as a structurally simplified bioisostere of β-carboline. Guided by the principles of multi-target drug design and combinatorial chemistry, we designed and synthesized a series of quinazoline-carbazole hybrids as dual TXNIP/DYRK1A inhibitors. Compounds PF-5 and PF-6 markedly attenuated palmitic acid (PA)-induced β‑cell injury by suppressing the TXNIP-NLRP3-IL-1β signaling axis. Meanwhile, compounds PF-6 and PF-8 enhanced β-cell proliferation via DYRK1A inhibition. Molecular docking confirmed PF-6 bound with high affinity to both targets, and ADMET predictions supported its drug-like properties. Thus, PF-6 emerges as a potential dual-target therapeutics for T2DM. In conclusion, PF-6 can be used as a potential new chemical entity against T2DM.

Unsaturated polyester resin (UPR) suffers from high flammability and the release of toxic smoke during combustion. Although intrinsically flame retardant UPR (FRUP2), containing low-oxidation-state phosphorus structures, exhibits excellent gas-phase flame inhibition, it inevitably aggravates incomplete combustion, leading to excessive smoke and CO release. To address this limitation, a novel flame retardant (phosphotungstic acid-modified zirconium phosphate (HPW/ZrP)) was synthesized and introduced into FRUP2 and its glass fiber-reinforced composites. At an optimal loading of 3 wt%, FRUP2-HPW/ZrP achieved a limiting oxygen index (LOI) of 24.2% and a UL-94 V-0 rating. Cone calorimetry revealed significant reductions in both fire and smoke hazards: the peak heat release rate (PHRR) and total heat release (THR) decreased by 20.28% and 9.10%, respectively, while total smoke production (TSP) and CO yield (COY) were reduced by 18.87% and 74.65%, compared with FRUP2. The enhanced performance is attributed to the strong acidic sites on HPW/ZrP, which catalyze the rapid formation of a dense and graphitized char layer, effectively inhibiting heat and mass transfer and mitigating the smoke toxicity induced by low-oxidation-state phosphorus. In addition, HPW/ZrP improved the mechanical performance of FRUP2. For glass fiber-reinforced composites, HPW/ZrP maintained excellent flame retardancy and smoke suppression without compromising tensile strength. This study provides an effective strategy to overcome the smoke toxicity issue of phosphorus-containing intrinsically flame retardant UPR, offering a promising pathway toward fire-safe, high-performance polymer composites.

The widespread emergence of antibiotic resistance necessitates the development of novel agents with unique mechanisms of action. Obafluorin (OB), a natural β-lactone antibiotic, is a covalent inhibitor of threonyl-tRNA synthetase (ThrRS), but the high conservation of the active site between prokaryote and eukaryote ThrRSs results in minimal selectivity, hindering the therapeutic potential of OB. Here, we report a structure dynamics-based design strategy that transforms OB into a selective antibacterial agent. OB inhibits human and bacterial ThrRSs with nearly equal potency due to identical binding modes. The nitrophenyl moiety of OB is proposed as a 'kinetic sensor' that discriminates between sensitive and resistant ThrRS paralogs. Guided by this insight, we designed a series of OB analogs through rational modification of this moiety. Among them, OB-D4 bearing a para-methoxyphenyl group in place of the nitrophenyl group, exhibited a 241-fold selectivity for bacterial over human ThrRS, along with a markedly improved safety profile with minimal cytotoxicity. In a murine skin infection model, OB-D4 effectively eradicated pathogens, resolving inflammation, and promoting wound healing. Together, this work establishes a 'kinetic sensor' strategy for achieving species selectivity, turning a fundamental challenge in drug discovery-high active-site conservation-into an exploitable opportunity based on dynamic differences.

Barocaloric effects (BCE) represent an appealing refrigeration technology and have attracted great interest recently. However, most BCE materials still cannot meet real-world refrigeration requirements because of their fixed phase transition temperature TC and the significantly high pressure required to drive a wide cooling temperature span. Here, we address these bottlenecks by engineering molecular channels in a SCO complex, Fe[L2]. Besides the observation of colossal and reversible BCE in Fe[L2], the designed molecular channels allow fast commutation of H2O and CH3OH, which enables the tunability of TC and creates a refrigeration window as wide as 80 K by simply altering the solvent atmosphere, as confirmed by SC-XRD, P-DSC, PXRD, Raman, and DFT calculations. Inspired by the proposed "solvent-caloric" effect, the refrigeration capacity at ambient pressure can be 9 times higher than that achieved at 100 MPa using conventional BCE methods, greatly boosting the universality for different BCE refrigeration scenarios. Our results demonstrate that the designed molecular channels in SCO complexes can influence the SCO transition properties and thereby bring forth singular caloric phenomena, offering new routes for orchestrating novel cooling materials.

Helicobacter pylori (H. pylori) infection poses a significant global health burden and is implicated in various chronic gastric diseases. However, current antibiotic therapies are limited by non-specific bacterial targeting, which often results in antimicrobial resistance and disruption of gut microbial homeostasis. To overcome these limitations, we developed a pH-responsive, self-sacrificing cascade nanozyme platform, ZnO2-CuNiS@G-Ch, for the targeted eradication of H. pylori. In the highly acidic gastric environment, ZnO2 rapidly decomposes to release Zn2+ and H2O2, initiating selective bacterial killing. Furthermore, the generated H2O2 triggers the cascade activation of CuNiS@G-Ch nanozyme, exhibiting multiple enzyme-like activities-peroxidase (POD), catalase (CAT), and oxidase (OXD) to locally generate reactive oxygen species (ROS) and O2, thereby amplifying the bactericidal effect. Notably, upon transiting to the neutral intestinal milieu, the degradation of ZnO2 was completely suppressed, effectively halting downstream nanozyme activity and preserving the gut microbiota. Comprehensive in vitro and in vivo studies confirmed the robust anti-H. pylori efficacy of ZnO2-CuNiS@G-Ch, alongside potent anti-inflammatory effects, gastric mucosal protection, and excellent biocompatibility. This work provides a selective, efficient, and microbiota-friendly strategy for H. pylori therapy, offering a promising alternative to conventional broad-spectrum antibiotics.

Clinically inspired combination therapy has become an important strategy for improving cancer treatment by integrating direct tumor cytotoxicity with immune regulation. However, conventional co-administration of multiple chemotherapeutic and immunomodulatory agents often suffers from pharmacokinetic mismatch, insufficient tumor accumulation, systemic toxicity, and limited durable antitumor immunity. Herein, we developed a triple-drug chemo-immunotherapeutic nanoformulation, DSPE-PEG-CS@MTO@CTX@JQ1, by employing a previously validated DSPE-PEG-chondroitin sulfate dual-targeting nanoliposomal platform to co-deliver mitoxantrone (MTO), cyclophosphamide (CTX), and the BRD4 inhibitor JQ1. This strategy was designed to translate the therapeutic logic of clinical combination chemotherapy into a synchronized nanodelivery system capable of coordinating tumor killing, immune activation, and immune escape suppression. Mechanistically, MTO served as an immunogenic cell death inducer to promote calreticulin exposure, HMGB1 release, and tumor antigen presentation; CTX was introduced to attenuate immunosuppressive regulation, particularly by reducing regulatory T-cell-associated inhibition; and JQ1 suppressed BRD4-dependent PD-L1 transcription to limit adaptive immune escape. The DSPE-PEG-CS liposomal shell functioned as a validated delivery vehicle to improve circulation stability, reduce premature drug leakage, and enhance CD44-mediated tumor targeting. The resulting nanoformulation exhibited favorable particle size, morphology, and drug-loading performance, while effectively promoting dendritic cell maturation, remodeling tumor immune microenvironment, and strengthening antitumor immune responses. By integrating clinically inspired triple-drug chemotherapy with immunogenic cell death induction, immunosuppression relief, and PD-L1 transcriptional suppression, this work provides a rational nanomedicine strategy for converting chemotherapy-induced tumor damage into sustained antitumor immune responses.

S-Adenosyl-l-methionine (SAM)-dependent methyltransferases (MTs) play important roles in many biological processes by catalyzing a methylation reaction. Proteins with a similar MT-fold to enable catalytic abilities rather than methylation were evidenced, but revealing these abilities appears to be a challenge to bioinformatics analysis unless experimental efforts are involved. Based on comprehensive investigations into MitM in the biosynthesis of mitomycins, the clinically important antitumor antibiotics, we report here that this MT catalyzes reactions more than methylation. MitM primarily acts as a C9a-O-MT for methylating the 6/5/5/3-fused aziridinomitosane (AMS) skeleton that is shared by many known mitomycin variables in C9 stereoselectivity and aziridine-N-methylation. Further, this MT can process AMS for C9a-O-methoxy elimination, aziridine hydrolysis/opening, and subsequent C1-O- and C2-N-methylations. Gene inactivation, biochemical characterization, substrate/product cocrystallization, and site-specific mutagenesis rationalized the mechanisms by which the MT-fold of MitM is repurposed to deliver such an extraordinary capability, facilitating the observation of a few new antitumor mitomycins that were not recognized previously in the producing strain. This study attracts attention to uncharacterized MT-fold proteins, which have millions of sequences in databases but remain to be appreciated in catalytic function.

Hepatocellular carcinoma (HCC) poses significant clinical challenges, including high recurrence, mortality, and drug resistance, underscoring the urgent needs for novel targeted therapies. Lin28B, an RNA-binding protein frequently overexpressed in HCC, promotes tumor progression by enhancing oncogenic signaling pathways and inhibiting the maturation of tumor-suppressive let-7 family miRNAs. However, due to the lack of conventional small-molecule binding pockets, Lin28B has long been considered an undruggable target. In this study, a series of pre-let-7-PROTACs were constructed by conjugating pre-let-7 family miRNAs and E3 ligase ligands. Most pre-let-7-PROTACs achieved efficient and specific degradation of Lin28B and restored endogenous mature let-7 expression, thereby suppressing HCC cell proliferation and migration, promoting apoptosis, and enhancing chemosensitivity. In a Huh-7 xenograft tumor model, pre-let-7-PROTACs exhibited significant synergistic antitumor effects when combined with sorafenib (SFB). This study confirmed that pre-let-7-PROTACs reduce tumor stemness by degrading Lin28B, offering a promising therapeutic approach for HCC.

Burn wounds present unique challenges for dressings due to severe vascular damage, irregular wound shapes, and excessive reactive oxygen species (ROS). In this work, we designed a bio-based multifunctional hydrogel dressing possessing antioxidant, antibacterial, and angiogenic properties. The hydrogel matrix was functionalized by embedding black phosphorus nanosheets (BPNS) coated with a tannic acid-copper ion complex (BPNS@TA-Cu), thereby imparting unique pH-dependent dual functions to the resulting composite. Specifically, under acidic microenvironments, it demonstrates a synergistic combination of photothermal therapy (PTT) and peroxidase-like (POD) activity, conferring potent antibacterial efficacy. In contrast, under neutral conditions, the material effectively scavenges reactive oxygen species (ROS) and reactive nitrogen species (RNS), thereby exhibiting outstanding antioxidant properties. The hydrogel's rapid self-healing and shape adaptability arose from a dynamic cross-linked network formed via borate ester bonds among gelatin (Gel), polyvinyl alcohol (PVA), cationic guar gum (CG), BPNS@TA-Cu, and borax. This adaptability allowed the dressing to conform to and fill irregular burn wounds, ensuring close contact. The hydrogel promoted full-thickness burn defect wound healing by facilitating granulation tissue formation, epithelial regeneration, and collagen deposition. Collectively, these findings establish the GPC-BTC hydrogel as a viable and promising multifunctional dressing strategy to accelerate burn wound healing.

Lipid nanoparticles (LNPs) currently represent the predominant delivery strategy for clinically approved nucleic acid drugs. However, the inherent limitations in targeting, low lysosomal escape efficiency, and potential immunogenic risks pose significant challenges to the broader applications of LNP technology. Vitamin A and spermine are endogenous small molecules that all have shown potentials for low toxicity and efficient drug delivery. In this study, we constructed a series of novel VA-linker-Sper lipids through the conjugation of vitamin A and spermine. With the helper lipid dioleoylphosphatidyl ethanolamine (DOPE), we successfully developed a nucleic acid delivery reagent, VA-6C-Sper/DOPE. Mediated by the vitamin A receptor, this reagent achieved highly efficient delivery of both siRNA and plasmids in hepatocellular carcinoma cells (HepG2) and retinal pigment epithelial cells (ARPE19). The cellular uptake and gene regulation effects with VA-6C-Sper were far superior exceeded those of the commercial transfection reagent Lipofectamine. This work provides a foundation for the nucleic acid drug treatment of ocular diseases that are dependent on vitamin A metabolism.

Core fucosylation, catalyzed by fucosyltransferase 8 (FUT8), plays critical roles in cancer progression, immune evasion, and drug resistance, making it a compelling therapeutic target. However, development of selective FUT8 inhibitors has been hindered by shared substrate specificity of fucosyltransferases. Here, we report the discovery of a previously unrecognized allosteric site on FUT8 and the development of a low-toxicity covalent inhibitor, CAIF (stearic acid-N-hydroxysuccinimide ester-dimethylimidazolium bromide), through structure-based drug design. High-throughput screening and crystallographic studies reveal that small molecules such as NH125 bind to a channel-like allosteric pocket, inducing conformational changes that disrupt FUT8 activity. Leveraging these insights, we design CAIF to covalently target lysine K216 within the allosteric site. CAIF exhibits minimal cytotoxicity and significantly inhibits core fucosylation and cancer cell invasion in cellular assays. This work establishes CAIF as a lead compound for further optimization and development, offering a framework for targeting glycosyltransferases through allosteric and covalent inhibition strategies.

Osteoporosis (OP) and its related fragility fractures represent a significant global health burden, primarily characterized by reduced bone mass, deteriorated microarchitecture, and compromised self-repair capacity. While current mainstream therapies focusing on anti-resorption and anabolic pathways can slow bone loss, they often fall short in reversing established skeletal deficits and, particularly, in facilitating fracture healing. Growing evidence underscores that angiogenesis is fundamentally coupled with osteogenesis, forming the cornerstone of bone homeostasis and injury repair. However, developing therapeutic strategies targeting this “vascular-bone” axis remains a relatively nascent and underexplored area in the clinical management of both systemic osteoporosis and osteoporotic fractures. This review aims to provide a comprehensive synthesis of dual strategies targeting angiogenesis for the treatment of systemic osteoporosis and the enhancement of osteoporotic fracture healing. We first analyze the pivotal role and regulatory networks of angiogenesis in maintaining bone homeostasis and within the fracture repair microenvironment. Subsequently, we systematically categorize and critically evaluate various intervention strategies based on this approach, including mesenchymal stem cells and their exosomes with paracrine functions, phytochemicals and traditional Chinese medicine compounds possessing dual regulatory activities, non-coding RNAs (miRNAs, lncRNAs, circRNAs) that modulate key signaling pathways, proteins or peptides with defined pro-angiogenic activity, repurposed clinical drugs with potential vascular-modulating properties, and non-invasive physical therapies. The article further compares and contrasts the application of these strategies for systemic bone mass restoration versus localized fracture repair, discussing differences in delivery methods, molecular targets, and expected outcomes. Finally, we address the current challenges in the field—such as target specificity, translational barriers, and the lack of robust clinical evidence—and outline future research directions. By integrating existing knowledge, this review seeks to provide a theoretical foundation and novel perspectives for developing next-generation, synergistic therapies centered on vascular regeneration, designed to concurrently improve bone mineral density and bone quality.

Androgenetic alopecia (AGA) is characterized by progressive hair loss caused by abnormal androgen levels in hair follicles, which has a substantial impact on both the physiological and psychological well-being of patients. The androgen receptor (AR) has been validated as an important target, and the local application of AR-targeting small-interference RNAs (siRNA) has been identified as a promising treatment for AGA. Nevertheless, the clinical utilization of RNAi therapy has been hampered by inefficient delivery, potential inflammatory responses, and poor in vivo retention capacity. Here, a series of spermine-derived ionizable lipids with varying alkyl chains (Sper-N, N = 8, 12, 16) were synthesized and subsequently coformulated with DSPC and a PEG-lipid to generate Sper-N/siRNA lipid nanoparticles. In vitro studies have demonstrated that Sper-12-based nanoparticles facilitate efficient siRNA delivery for AR gene silencing as well as the internalization of ASOs and plasmid DNA. Further in vivo studies with intradermal administration of Sper-12/siAR nanoparticles have confirmed effective suppression of aberrant AR protein in androgenetic alopecia model mice, promotion of hair follicle proliferation, and alleviation of hair loss symptoms. The Sper-12/siRNA nanoparticles provide a versatile delivery platform to advance siRNA-based therapeutics for androgenetic alopecia.

Infected burn wounds are characterized by bacterial invasion, oxidative stress, and persistent inflammation, which severely impair tissue regeneration. Herein, we report a crosslinker-free, hydrogen-bonded cationic guar gum hydrogel (CBBM) co-loaded with berberine (BBR) and MnO2-coated black phosphorus nanosheets (BPNS@MnO2) for the microenvironment-adaptive treatment of infected burn wounds. The dynamic guar gum network endowed the hydrogel with injectability, self-healing ability, and conformal adaptability. BPNS@MnO2 exhibited pH-dependent enzyme-like activities, including OXD-like antibacterial activity under acidic conditions and SOD-/CAT-like ROS-scavenging activity under near-neutral conditions and endowed the hydrogel with NIR-triggered photothermal responsiveness. Moreover, NIR irradiation further enhanced the antibacterial efficacy and moderately enhanced BBR release from the hydrogel. In vitro, CBBM combined with NIR irradiation achieved potent antibacterial efficacy against S. aureus and E. coli under the tested conditions and reduced intracellular ROS levels. In vivo, the CBBM + NIR treatment accelerated infected burn wound healing, achieving a wound closure rate of 97.53 ± 2.01% by day 14, accompanied by reduced inflammation, enhanced collagen deposition, and increased expression of the angiogenesis-related markers VEGF and CD31. These results demonstrate that the CBBM hydrogel is a promising multifunctional guar gum-based dressing for infected burn wound healing by integrating local drug delivery, catalytic regulation, and photothermal activation.

Cotton fabrics are highly flammable cellulose-based textiles that are prone to rapid flame spread and smoldering, creating serious fire-safety risks. Hydrogel coatings offer a promising route for textile fire protection because their water-rich networks can absorb heat through evaporation and subsequently form thermally insulating char barriers. However, many reported hydrogel coatings require complex preparation, external curing, or long processing times, which limits their rapid deployment. Herein, a rapidly deployable bio-based organic hydrogel coating, denoted as HP hydrogel, was fabricated at room temperature through electrostatic self-assembly between quaternized chitosan (HTCC) and sodium phytate (PA-Na). The optimized coating could be directly applied onto cotton fabrics after fast gelation, combining water retention, substrate adhesion, flame retardancy, and short-term thermal shielding. PA-Na promoted the thermal degradation regulation and char-forming ability of the HTCC network, enabling the coated cotton fabric to reach a limiting oxygen index of 31%. Micro-combustion calorimetry showed that the H1P1 hydrogel reduced the peak heat release rate and total heat release by 32.9% and 34.4%, respectively, compared with the PA-Na-free hydrogel. Residual char analyses confirmed the formation of a compact phosphorus-containing carbonaceous layer, indicating a dominant condensed-phase flame-retardant mechanism. In direct-flame thermal protection tests, the H1P1 hydrogel protected skin-surrogate tissue for 120 s under exposure to a 1300 °C flame, while maintaining the subcutaneous temperature below 55 °C. This work presents a simple and rapidly applicable bio-based hydrogel coating strategy for improving the flame retardancy and short-term fire protection of cellulose-based textiles.