Cancer severely endangers human health, and traditional single-therapy approaches have limitations. This study developed a hyaluronic acid (HA)-targeted self-assembled nanodrug system (DOX/CGFH) for delivering doxorubicin hydrochloride (DOX). The red-emissive carbon dots (R-CDs) exhibited both glutathione oxidase-like activity and photothermal/imaging capabilities, enabling glutathione (GSH) depletion in the tumor microenvironment. GF nanoparticles, synthesized at an optimal ratio, demonstrate high Fenton catalytic activity and near-infrared (NIR) light irradiation, and NIR irradiation significantly enhance the generation of ·OH. This system displayed outstanding photothermal performance (29.7

Rhabdomyolysis-induced acute kidney injury (RM-AKI) is a life-threatening clinical condition characterized by excessive myoglobin release, leading to kidney tubular obstruction, oxidative stress, and iron-mediated lipid peroxidation. However, current therapies fail to effectively suppress oxidative stress cascades and lack kidney targeting. Herein, we developed a kidney-targeted nanodrug delivery system with multimodal antioxidant functionality (DFO@SOC) for RM-AKI therapy. Using antioxidant capacity as the decisive screening criterion, Se/S co-doped onion-derived carbon dots (SOC) were identified as the optimal nanocarrier through systematic natural polyphenol precursor selection and heteroatom-doping optimization. SOC exhibited pronounced superoxide dismutase-like and catalase-like activities. The iron chelator deferoxamine (DFO) was subsequently loaded onto SOC, yielding uniformly sized, negatively charged DFO@SOC nanoparticles. In vitro studies demonstrated efficient cellular uptake, robust intracellular scavenging of reactive oxygen species (ROS) and iron ions, and negligible cytotoxicity. In an RM-AKI mouse model, DFO@SOC selectively accumulated in injured kidneys. Notably, Sound Touch Visco-elastography (STVi) and Quantitative Tissue Scattering Coefficient (QTSC) enabled noninvasive and real-time evaluation of therapeutic efficacy with kidney stiffness decreasing significantly from ∼14 to 7 kPa. Combined biochemical and histopathological analyses, DFO@SOC treatment significantly reduced Scr from ∼193.31 to ∼93.82 μmol/L and blood urea nitrogen (BUN) from ∼52.99 to ∼30.68 mmol/L compared to the model group. In summary, the synergistic antioxidant and iron-chelation effects of DFO and SOC, establishing DFO@SOC as a promising nanotherapeutic strategy for RM-AKI.

Rationale: Immunotherapy has emerged as a crucial component in cancer treatment, particularly for the long-term reduction of cancer metastasis and recurrence. However, its development is hindered by limited activation of cellular immune response and suboptimal delivery of vaccine to antigen-presenting cells. Methods: The vaccine was encapsulated within mesoporous silica nanoparticles, followed by functionalization by mannose and phenylboronate ester (MSN-NH-DPM), which facilitates targeting antigen-presenting cells via mannose receptors and enables intracellular delivery through endosomal escape, thereby activating cellular immunity. The nanoparticles were then integrated into chitosan microneedle patches (MNs), which are engineered to deliver the nanoparticles into the skin that is abundant in immune cells, and improve the immune response through the adjuvant properties of chitosan. Results: The chitosan MNs incorporating MSN-NH-DPM (CTS-MN@MSN-NH-DPM) significantly activated the cellular immune response through the MHC-I pathway. The antigen-presenting cells that uptake the vaccine migrated to nearby lymph nodes, inducing systemic immunity to eliminate cancer cells. Compared with subcutaneous injection, the application of CTS-MN@MSN-NH-DPM significantly inhibited the growth of B16/OVA melanoma tumors and extended the survival time of the melanoma mouse model. Conclusions: The MNs with targeted and intracellular delivery represent a promising platform for various vaccines to improve the cellular immune response, thus providing a potential solution for cancer treatment.

Photothermal therapy (PTT) has emerged as a promising strategy with significant potential for clinical translation in oncology, owing to its advantages such as minimal side effects, high selectivity, and excellent spatiotemporal controllability. The core efficacy of this therapeutic modality relies on the synergy between near-infrared (NIR) light and high-performance photothermal agents (PTAs). As key mediators of energy conversion, the properties of PTAs directly determine the photothermal conversion efficiency (PCE) and the ultimate therapeutic outcome. Accordingly, this paper systematically summarizes the structural characteristics and functional properties of various PTA materials, including noble metal-based, carbon-based, polymer-based, and organic small-molecule PTAs. Furthermore, it reviews recent progress regarding high-performance PTAs featuring high PCE, excellent biocompatibility, and efficient tumor targeting capabilities. To address the limitations of monotherapy PTT in treating complex tumors, this paper focuses on various synergistic therapeutic strategies. The combination of PTT with chemotherapy, photodynamic therapy (PDT), and chemodynamic therapy (CDT) utilizes thermal effects to promote drug release and enhance reactive oxygen species (ROS) generation. Integration with immunotherapy and gene therapy (GT) can effectively activate systemic anti-tumor immune responses and facilitate nucleic acid delivery. Additionally, combination with gas therapy (GAT) improves the tumor microenvironment by inhibiting heat shock protein expression, thereby significantly enhancing tumor thermosensitivity. In conclusion, the development of novel, multifunctional, and intelligent PTAs that meet clinical translation requirements remains a critical direction for driving the further advancement of PTT.

Respiratory syncytial virus (RSV) poses a critical threat to infants, yet vaccine and antibody development remains challenged by safety risks and antigenic variability. Here, we present a prophylactic strategy leveraging two human neutralizing antibodies, 1A2 and 1B6, which target distinct, conserved epitopes on the RSV prefusion F (pre-F) protein. Cryo-electron microscopy (cryo-EM) structural analysis revealed that 1A2 binds a "waist" epitope spanning antigenic sites IV/V, whereas 1B6 engages a "head" epitope bridging sites Ø/II/V, collectively stabilizing the pre-F trimer to block conformational transitions critical for viral entry. In vitro escape mutagenesis demonstrated that the 1A2/1B6 cocktail can resist viral escape (>20 passages), contrasting with rapid resistance to nirsevimab (targeting site Ø) and single antibodies [1A2: Gly446→Glu (G446E); 1B6: Gln94→Arg (Q94R) or Gln94→Lys (Q94K)]. Fc engineering extended serum half-lives while ablating effector functions, addressing potential safety concerns. Last, prophylactic administration in rodent models conferred robust protection against RSV A and B strains, including nirsevimab-resistant variants, with a 296-fold reduction in lung viral titers. This dual-epitope approach overcomes limitations of current monotherapies by combining high conservation, synergistic potency, and escape resilience, positioning it as a valuable immunoprophylactic candidate for pediatric RSV prevention.

Lyotropic liquid crystals (LLCs) are a promising class of self-assembled systems with highly tunable topologies. They offer considerable potential for long-acting drug delivery because of their sustained-release capabilities and facile preparation. However, molecular mechanisms underlying LLC formation and the effects of topology on drug release remain poorly understood. In this study, LLC systems with distinct topologies were constructed using soya phosphatidylcholine and glyceryl dioleate. The release behaviors of three model compounds with different hydrophilicities were systematically investigated through in vitro and in vivo experiments. Additionally, molecular dynamics simulations were employed to visualize the lipid self-assembly and elucidate drug release mechanisms at the molecular level. The results reveal that drug release is synergistically regulated by the LLC structure and intermolecular interactions between drugs and lipids (soya phosphatidylcholine and glyceryl dioleate). Notably, molecular dynamics simulations provide ultramicroscopic insights into LLC formation and drug release mechanisms, complementing experimental observations and offering perspectives that are difficult to achieve using conventional techniques.

Persistent oxidative stress and excessive inflammatory responses severely impede the healing of infected wounds, while traditional dressings struggle to simultaneously address antimicrobial, anti-inflammatory, and tissue regeneration concerns. A multifunctional hydrogel integrating antibacterial, antioxidant, and photothermal functionalities was designed herein for the treatment of infected wounds. Using a soft-template method, we synthesized mesoporous polydopamine nanoparticles (MPDA) and chelated copper ions during the polymerization. Cu@MP nanoparticles with high photothermal conversion efficiency were prepared. After incorporating the Cu@MP nanoparticles into the acrylamide polymerization system, a composite hydrogel Cu-PAM with a three-dimensional porous structure was formed. The hydrogel exhibited mechanical properties and tissue adhesion, which could adapt to the deformation of the wound. In vitro assays verified that the Cu-PAM hydrogel eliminated over 99.8% of both E. coli and S. aureus upon near-infrared (NIR) light exposure. The hydrogel exhibited efficient clearance of reactive oxygen species (ROS), while its ability to promote tube formation in HUVECs was also evaluated. Animal experiments confirmed that the hydrogel, in combination with photothermal therapy (PTT), significantly promoted the healing of S. aureus-infected wounds, facilitated orderly collagen deposition, and regulated inflammation. By combining the multifunctional hydrogel with PTT, the Cu-PAM hydrogel demonstrated extensive potential for treating infectious wounds.

It is imperative to adopt immune strategies that provide effective protection at the mucosal entry points of pathogens. Direct mucosal vaccination can effectively induce local mucosal immune responses and activate systemic mucosal immunity. However, the low uptake of antigens by antigen-presenting cells due to the mucus layer and epithelial barriers limits the effectiveness of vaccines. The neonatal Fc receptor (FcRn), known as a “mucosal gateway,” is thought to enhance drug uptake in intestinal epithelial cells. The study found that milk-derived exosomes (ME) can effectively utilize a “hitchhiking” strategy by encapsulating subunit antigens (such as ovalbumin, OVA) combined with immunostimulatory mesoporous silica nanoparticles (MSN) to create an oral vaccine that efficiently traverses the intestinal epithelial barrier and reaches the mucosal lamina propria. Our findings demonstrate that OVA/MSN@ME effectively maintains the oral stability of antigens and facilitates their translocation to the lamina propria, preliminarily suggesting an FcRn-mediated transport mechanism. This process subsequently triggers robust immune responses within gut-associated lymphoid tissues. These results indicate that the MSN@ME composite system is a promising delivery strategy for targeting mucosal epithelial cells, offering a potent means to enhance mucosal immunity against infectious diseases.

Oxidative stress triggered by excessive accumulation of reactive oxygen species (ROS) in vivo represents a common pathological basis for various diseases. Therefore, the development of safe and efficient antioxidants to eliminate excess ROS and counteract oxidative stress holds significant research potential. In recent years, carbon dots (CDs) have emerged as a novel class of carbon-based nanomaterials whose antioxidant activity has attracted widespread attention due to their excellent biocompatibility, low toxicity, and ease of functionalization, offering new strategies to combat oxidative stress. Although numerous excellent reviews on CDs have been published, there is still a lack of systematic review specifically focused on antioxidant CDs. This article summarizes the primary antioxidant mechanisms of CDs, including free radical scavenging, enzyme-like activities, and regulation of cellular signaling pathways. Furthermore, strategies for enhancing the antioxidant activity of CDs are discussed from the perspectives of synthesis process optimization, functional design, selective radical scavenging, and stimulus-responsive regulation, providing new insights for the design of more effective antioxidant CDs. Recent advances in the biomedical applications of antioxidant CDs are reviewed. Additionally, the in vivo metabolism, biodegradation, and biosafety of CDs are discussed. Finally, current challenges in this field are addressed, and future development prospects are outlined

Cuproptosis, a copper-dependent programmed cell death pathway, presents a paradoxical duality in oncology: essential for tumor proliferation yet lethal upon dysregulated accumulation. Despite its therapeutic promise, three fundamental barriers persist: (1) fragmented understanding of cuproptosis-TME crosstalk (e.g., hypoxia/autophagy-driven resistance), (2) absence of synergistic frameworks integrating five major cell death pathways (apoptosis/ferroptosis/pyroptosis/necroptosis/autophagy), and (3) translational chasm between nanocarrier design and clinical needs. This review establishes a tripartite mechanistic hierarchy to resolve these limitations: 1) Molecular dimension: Decodes the "Copper Threshold-TME Metabolic Phenotype", correlating copper flux with GSH depletion, lactate dynamics, and immune reprogramming; 2) Delivery dimension: Proposes stimuli-responsive nanocarrier classification (pH/H₂O₂/enzyme-triggered) under "spatiotemporally controllable copper delivery" principles; 3) Clinical dimension: Introduces "Four Translation Pillars" (biomarker validation, hepatoprotection, and nanopharmacokinetics) to bridge preclinical models and human trials. Critically, we will discuss the safety and therapeutic value of cuproptosis, and objectively evaluate the pros and cons of cuproptosis. These innovative perspectives are strategically designed to accelerate the further study of cuproptosis, thereby promoting warrant rigorous mechanistic validation and clinical assessment to ensure efficacy and safety.

Pancreatic dysfunction drives type 2 diabetes mellitus (T2DM), yet current therapeutic strategies inadequately address pancreatic insulin secretory failure. Here, we developed curcumin-loaded Momordica charantia L.-derived extracellular vesicles (CUR@McVs) to investigate the therapeutic potential of McVs in T2DM management. McVs enhanced the stability of CUR through lipid bilayer encapsulation, overcame multiple gastrointestinal absorption barriers, and achieved selective pancreatic accumulation via lymphatic trafficking. Integrated proteomic and molecular docking analyses revealed that McVs facilitated pancreatic targeting through Axl/Myoferlin receptor-mediated interactions. McVs treatment activated Akt/Nrf2/Bcl-2 signaling cascades, reducing oxidative stress, modulating cell-cycle checkpoints, and inhibiting beta-cell apoptosis. The combined action of McVs and encapsulated CUR significantly restored glucose-stimulated insulin secretion to 76.6 % of non-diabetic levels in vitro. In T2DM mice, CUR@McVs showed 9.47-fold higher pancreatic accumulation compared to free CUR, effectively normalizing blood glucose levels and reducing pancreatic oxidative stress. In contrast to conventional glucose-lowering agents, CUR@McVs fundamentally restored insulin secretion by regulating the pancreatic microenvironment. Notably, compared to synthetic nanocarriers with complex manufacturing processes and residual solvent risks, McVs offer scalable production and demonstrated safety upon repeated administration, underscoring their clinical translation potential. This plant-based nanoplatform establishes a novel paradigm for precision diabetes therapeutics, elucidating cross-kingdom communication mechanisms between plant-derived extracellular vesicles and mammalian systems.

Mesoporous carriers have gained significant attention for enhancing the solubility and bioavailability of Biopharmaceutics Classification System (BCS) Class II drugs. However, the contribution of mesoporous carriers with varying morphologies to the physical stability of these drugs is not well-defined. In this work, mesoporous carbon nanoparticles (MCN) and hollow carbon mesoporous nanoparticles (HMC) were prepared, while the weakly acidic Indomethacin (IMC) and alkaline Celecoxib (CXB) were incorporated into these carriers in the amorphous state by the solvent evaporation method. Notably, HMC demonstrated superior drug loading efficiencies (approximately 43%) for both IMC and CXB owning to its hollow structure. The mesoporous drug loading systems significantly enhanced dissolution rates in comparison with both self-made amorphous drugs and raw drugs. Furthermore, under accelerated and long-term storage conditions, the mesoporous carriers effectively prevented drugs loaded from crystallization, maintaining constant dissolution profiles for over 12 months. Intriguingly, CXB exhibited a slower rate of crystallization after loading into the mesoporous carriers, likely due to the formation of hydrogen bonds between the carbonaceous carrier material and the amino groups of CXB. Compared with loaded drugs, the self-made amorphous drugs exhibited a crystallinity increase beyond 60% within the initial month. Collectively, these findings highlighted the potential of mesoporous carbon carriers to elevate the dissolution behaviors of BCS Class II drugs while preserving the physical stability of the loaded amorphous drugs.

Combination therapies have attracted significant attention because they address the limitations of monotherapy while improving overall efficacy. In this study, we designed a novel nanoplatform, named GOx@Fe-DMSN@PDA (GFDP), by integrating Fe2+ into dendritic mesoporous silica nanoparticles (DMSN) and selecting glucose oxidase (GOx) as the model drug loaded into the DMSN pores. Additionally, we coated the surface of the DMSN with polydopamine (PDA) to confer pH/near infrared (NIR) light-responsive controlled-release behavior and photothermal therapy (PTT). The introduction of Fe2+ into the DMSN framework greatly improved biodegradability and enhanced the peroxidase (POD)-like activity of GFDP. In addition, GOx could consume glucose and generate hydrogen peroxide (H2O2) within tumor cells to facilitate starvation therapy and enhance cascade catalysis. The PDA coating provided the DMSN with an intelligent response release ability, promoting efficient photothermal conversion and achieving the PTT effect. Cellular tests showed that under NIR light irradiation, GFDP exhibited a synergistic effect of PTT-enhanced starvation therapy and cascade catalysis, with a half-maximal inhibitory concentration (IC50) of 2.89 mu g/mL, which was significantly lower than that of GFDP without NIR light irradiation (18.29 mu g/mL). The in vivo anti-tumor effect indicated that GFDP could effectively accumulate at the tumor site for thermal imaging and showed remarkable synergistic therapeutic effects. In summary, GFDP is a promising nanoplatform for multi-modal combination therapy that integrates starvation therapy, PTT, and cascade catalysis.

Weak response is the bottleneck for subunit prophylactic vaccines to trigger efficient immunization. The emergence of highly effective adjuvants will revolutionize. Considering that genomic epigenetic reprogramming plays an important role in the immune response, we herein present an minimalist epigenetic nano-adjuvant gMSN constructed of β-glucan-modified functional mesoporous silica (MSN), which we term as OVA/gMSN after loaded with the model antigen ovalbumin (OVA). Oral administration of OVA/gMSN ensures that enough antigen reach dendritic cells (DCs) in intestinal mucosal lymphoid follicles via intestinal M cells while relying on gMSN to exhibit good adjuvant properties to trigger an effective systemic co-mucosal immune response. gMSN upregulates genes associated with aerobic glycolysis, promoting metabolic reprogramming in DCs and enhancing the expression of genes related to DC activation, cross-presentation, maturation, and migration. Simultaneously, it increases the accumulation of key epigenetic markers H3K27ac, H3K4me1, and H3K4me3. ATAC-seq results reveal enhanced chromatin accessibility of key immune genes, such as Il2rα1, Il18r1, and Cd83, in gMSN-treated DCs. This integrative molecular mechanism demonstrates that gMSN induces epigenomic remodeling in DCs after oral administration, showcasing the potential of combining epigenetic adjuvants and nanotechnology in oral vaccine design, and providing new directions and a theoretical basis for vaccine adjuvant development.

Recently, protein biologics have shown unique advantage in tumor treatment, but they include limitations like cell membrane barrier and poor tumor penetration. To overcome these predicaments, a novel type of red light carbon dots (CDs) nanozyme (Fe(III)-CDs) was designed, featuring an amino acid-like "edge" and a specialized FeN4-coordinated nanocatalytic "core". Fe(III)-CDs and glucose oxidase (GOx) was used to form cascaded catalytic nanosystem FG to enhance reactive oxygen species (ROS) production efficiency. Meanwhile, the edge structure of Fe(III)-CDs exhibited strong affinity for the amino acid transporters ASCT2/LAT1, which were highly expressed in tumor cells. As a result, the transmembrane transport efficiency of GOx was significantly improved following the formation of FG. Then, hyaluronic acid (HA) was used to coat FG to obtain FG@HA, enabling controllable catalytic activity and longer circulation time. Encouragingly, in vitro/vivo results demonstrated that FG could effectively enhance the GOx transmembrane transport. Moreover, FG@HA exhibited controlled depolymerization with enhanced tumor penetration and excellent cascaded enzymatic/photothermal combined therapeutic effects with fluorescent tracing. Importantly, this study innovatively disassembled CDs nanozyme into characteristic "edge" and catalytic "core" to further understand the interaction with cells and catalytic mechanism, which provided additional support for guiding the CDs nanozyme design at molecular level.

Mesoporous silica nanoparticles (MSNs) are thought to be an attractive drug delivery material because of their advantages including high specific surface area, tunable pore size and morphology, easy surface modification and good biocompatibility. However, as a result of the poor biodegradability of MSNs, their biomedical applications are limited. To break the bottleneck of limited biomedical applications of MSNs, more and more researchers tend to design biodegradable MSNs (b-MSNs) nanosystems to obtain biodegradable as well as safe and reliable drug delivery carriers. In this review, we focused on summarizing strategies to improve the degradability of MSNs and innovatively proposed a series of advantages of b-MSNs, including controlled cargo release behavior, multifunctional frameworks, nano-catalysis, bio-imaging capabilities and enhanced therapeutic effects. Based on these advantages, we have innovatively summarized the applications of b-MSNs for enhanced tumor theranostics, including enhanced chemotherapy, delivery of nanosensitizers, gas molecules and biomacromolecules, initiation of immune response, synergistic therapies and image-guided tumor diagnostics. Finally, the challenges and further clinical translation potential of nanosystems based on b-MSNs are fully discussed and prospected. We believe that such b-MSNs delivery carriers will provide a timely reference for further applications in tumor theranostics.

There had been increasing interest in utilizing mesoporous silica nanoparticles (MSNs) to enhance hydrophilicity and improve bioavailability of Biopharmaceutical Classification System (BCS) class II drugs. Several commercial mesoporous silica excipients (CMSEs) with these functions had been approved as pharmaceutical adjuvants. This study comprehensively compared dendritic MSN (DMSN) carriers with CMSEs in multiple aspects, including specific surface area, pore size, drug loading capacity, and bioavailability enhancement for BCS class II drugs with different characteristics. Experimental results demonstrated DMSN's superiority over CMSEs in drug loading, in vitro dissolution rate, and bioavailability enhancement. DMSN achieved up to 40 % drug loading capacity, while CMSEs reached only 17 % maximum capacity under identical amorphous drug loading conditions. The universal applicability of DMSN for solubilizing BCS class II drugs was validated using three distinct drug models: weakly acidic drug-indomethacin (IMC), traditional Chinese medicine extract-MagnoliaofficinalisRehderetWilson (MAG), and basic drug-carvedilol (CAR). Accelerated stability testing with multiple characterization systematically confirmed that DMSN-based solid dispersion systems provided superior protection for BCS class II drugs. These findings prove DMSN as an exceptional carrier system for BCS class II drugs, offering new perspectives and methodologies for the exploration of mechanisms to improve the stability of solubilization.

severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) bivalent vaccines show potential against variants but lack a full understanding of the immunological mechanisms that drive broadly neutralizing antibodies (bnAbs). This study explored the immunogenicity of a bivalent vaccine in rhesus macaques, containing spike (S) proteins from the prototype (Sprototype) and chimeric S protein (S1628x). The vaccine induced bnAbs against multiple variants, including challenging subvariants like EG.1, BA.2.86, and JN.1. The monomeric S protein exposed less accessible regions within the receptor-binding domain (RBD) "inner face" and "NTD face" and subdomains 1, eliciting a diverse array of bnAbs against various Omicron subvariants. Notably, antibodies targeting the conserved RBD inner face, such as 4A5, showed potent neutralization across all tested variants. Structural analyses provide insights into the broad protectiveness of these vaccine-elicited nAbs. This study underscores the potential of bivalent vaccines with monomeric spike proteins to confer broad-spectrum immunity, offering a promising direction for future SARS-CoV-2 universal vaccine design.