Biomaterials for drug delivery must be biodegradable, nontoxic, and must not trigger inflammatory or immune responses. Silk fibroin (SF) is a natural polymer with exceptional mechanical strength and notable biological properties. In this study, the immunogenicity and inflammatory responses of silk fibroin nanoparticles (SFNPs) were characterized in primary human cells for the first time. SFNPs with a mean particle size of 213 ± 9 nm were synthesized and characterized. Primary human immune cells were exposed to SFNPs at concentrations ranging from 0.1 to 0.01 mg/mL. Cell viability remained above 80% under the tested conditions. No significant immune recognition was detected. Additionally, the levels of key pro-inflammatory proteins, including inducible nitric oxide synthase, pro-interleukin-1β, and cyclooxygenase-2, did not show significant upregulation compared to the control. Biodegradability assays demonstrated that SFNPs underwent degradation within 20 days, under physiological conditions. These findings indicate that SFNPs exhibit bio-inert behavior and highlight the significant advantages of SF as a biomaterial for biomedical applications. Owing to these properties, SFNPs represent a versatile biomaterial for the next-generation of drug delivery systems, offering substantial potential for improving clinical outcomes across a wide range of therapeutic areas.
Acute kidney injury (AKI) was a common clinical emergency with serious complications, and its treatment remains challenging. Here, we designed a biocompatible, ultrasound-captured nanomachine (NTMCH) that proactively delivered carbon monoxide (CO) under ultrasound. This system achieved kidney protection and enhanced renal clearance in a mouse model of AKI. The nanomachine was fabricated by coating niobium on one side of amine-functionalized mesoporous TiO2, followed by dimanganese decacarbonyl (Mn2(CO)10) loading and hyaluronic acid modification. Asymmetric CO release both propelled the nanomachine and acted as a therapeutic gas. At the kidney injury site, ultrasound triggers CO release, which stimulates ROS generation from mesoporous titanium dioxide (MTD), cascading Mn2(CO)10 activation. This enhanced CO diffusion and renal clearance in synergy with Nb. This ultrasound-responsive nanomachine offered outstanding potential for kidney protection via CD44 regulation, with findings that could advance future clinical development.
Peritoneal metastasis is a leading cause of mortality in end-stage gastric cancer and remains poorly responsive to conventional chemotherapy. To address this unmet need, Janus dendron-modified phthalocyanines were developed as tumor-targeted photosensitizers for photodynamic therapy (PDT). A series of Janus dendron-modified phthalocyanines with tailored surface functionalities s synthesized, exhibiting spontaneous self-assembly into nanoparticles with augmented fluorescence, amplified reactive oxygen species (ROS) production, and improved tumor-targeting specificity. Among them, the lead compound TT1-4PYR, bearing pyrrolidone moieties, demonstrated ascites-derived protein corona and macropinocytosis-mediated cellular internalization, enabling deep penetration and selective accumulation in peritoneal metastasis lesions. Comprehensive evaluation in vitro, in vivo, and in human-derived gastric cancer organoid models confirmed its potent and targeted photodynamic cytotoxicity, effectively suppressing tumor progression without inducing systemic toxicity, achieving a favorable biosafety profile. These results highlight TT1-4PYR as a promising and deep-penetrating therapeutic agent for peritoneal metastasis, with potential applicability to other metastatic malignancies.
Watertight dural closure is essential for successful cranial and spinal surgery but remains a major clinical challenge due to persistent cerebrospinal fluid (CSF) leakage and associated complications. Conventional dural suturing is particularly challenging in cases involving fragile dura or anatomically complex defects, while existing sealants often suffer from delayed gelation, inadequate wet-tissue adhesion, and excessive swelling that may cause neural tissue compression. Herein, we report an injectable, biocompatible, low-swelling bioadhesive sealant (DLSS) based on N-hydroxysuccinimide-activated tetra-armed poly(ethylene glycol) and amine-functionalized gelatin for sutureless dural repair. The optimized hydrogel exhibits rapid in situ gelation, robust mechanical properties, effective wet-tissue adhesion, high burst pressure resistance, and limited swelling (13.2% volumetric swelling ratio in artificial CSF). Furthermore, DLSS demonstrates cytocompatibility and hemocompatibility, supports fibroblast migration, and undergoes controlled biodegradation. Ex vivo testing on rabbit dura demonstrated rapid and durable sutureless sealing of dural defects by DLSS. In vivo evaluation in rat cranial and spinal dural defect models demonstrated that DLSS enabled effective dural closure and tissue repair without detectable CSF leakage, showing improved performance compared with commercial fibrin glue. Its translational potential was validated in clinically relevant beagle models. Collectively, DLSS offers a promising strategy for sutureless dural repair.
Despite increasing awareness of molecular subtypes of breast cancer, this heterogeneous malignant disease is still one of the leading causes of cancer death in women worldwide. Although receptor status may define the precise therapeutic targets, treatment of triple-negative breast cancer (TNBC) relies mainly on chemotherapy with accompanying side-effects. Thus, there is a need for the design and testing of more effective drug delivery systems and drug combinations. In this study, biomimetic self-assembled bovine serum albumin (BSA) capsules (Cs) co-loaded with a new drug combination, namely two drugs tanespimycin (T) and dasatinib (D), and natural compound quercetin (Q), were fabricated, and their anti-breast cancer effects were assessed. (T-D-Q)-BSA Cs were more active against TNBC cells compared to other types of breast cancer. Encapsulated drugs potentiated apoptotic cell death in TNBC cells compared to the effect of the free three-drug formulation. In TNBC cells with mutated TP53, (T-D-Q)-BSA Cs also induced necroptotic cell death accompanied by RAP1-mediated stimulation of NFκB activity and IL-6-related proinflammatory response. (T-D-Q)-BSA Cs also inhibited TNBC-based tumor growth in two zebrafish xenograft in vivo models. In conclusion, the efficacy of (T-D-Q)-BSA Cs as a novel therapeutic strategy to eradicate TNBC in vitro and in vivo was demonstrated.
The cGAS-STING pathway is a pivotal therapeutic target for antitumor immunity, yet clinical translation of its small-molecule agonists is hindered by poor tumor specificity, suboptimal pharmacokinetics, and systemic off-target effects. Here, we report a nanocatalytic strategy based on a tumor microenvironment (TME)-responsive iron-oxygen-vanadium metal-organic framework (MIL-88B(Fe─O─V)) that enables tumor-specific cGAS-STING activation via catalytic phase separation for targeted immunotherapy in spinal metastasized breast cancer. Specifically, MIL-88B(Fe─O─V) undergoes disassembly within the acidic TME to release iron ions and polyoxovanadate (POV). Iron ions enable catalytic reactive oxygen species (ROS) generation to release double-stranded DNA (dsDNA) and induce immunogenic cell death (ICD). Critically, we demonstrate for the first time that POV potently promotes liquid-liquid phase separation (LLPS) of cGAS, enhancing its affinity for dsDNA and amplifying STING pathway activation in dendritic cells (DCs) without systemic immune dysregulation. Such combinational ICD induction and LLPS-driven cGAS activation synergistically boost DC maturation, cytotoxic T-cell responses, and establish durable antitumor immunity. In spinal metastasis models, MIL-88B(Fe─O─V) not only achieves robust tumor regression and prolonged survival, but also mitigates cancer-related pain via IFN-β-mediated suppression of TRPV1 channel activity. Our findings unveil a paradigm of nanocatalytic STING activation for advanced metastatic cancer metalloimmunotherapy and cancer pain alleviation.
Fluorescence‑guided surgery using activatable probes is promising, but single‑channel probes often give false negatives-especially in pancreatic cancer due to tumor heterogeneity and limited imaging depth. Here, we built a universal charge-switching gated PET platform based on cyanine dyes bearing a meso-quinolinium moiety. This platform-by decoupling quenching from the recognition group-enabled the construction of two structurally analogous, hypoxia-activatable near-infrared (NIR) probes (Cy5-Ql-NTR and Cy7-Ql-NTR), which have comparable responsive kinetics (sensitive, fast-responding, and low-background), good water solubility and favorable renal clearance, but differ in tissue imaging depth: the former generates brighter signals in superficial regions, while the latter enables deeper tissue penetration and serves as a self-calibration reference. Notably, compared to a single probe, the combined metabolic distribution of the two probes covers a broader range of tumor target tissues. Through their dual-channel imaging, depth-dependent signal attenuation is corrected, and blind spots during probe delivery are reduced. Compared to single-channel fluorescence-guided surgery in subcutaneous pancreatic cancer and orthotopic pancreatic tumor, the dual-channel approach yielded clean margins, preserved significantly more normal tissue, and left no residual tumor on histology. This self-referenced detection strategy suppresses false negatives in single-channel detection, offering a practical and optimized solution for intraoperative guidance in pancreatic cancer.
Developing a "full-cycle" strategy that integrates both treatment and prophylaxis remains a central challenge against nasopharyngeal carcinoma (NPC). Here, a biomimetic nanovaccine (CDC/Toy@CCM) is designed by coating toyocamycin (Toy)-loaded redox-responsive carbon dot clusters (CDCs) with homologous cancer cell membranes (CCMs). The obtained nanovaccine exhibits an average size of 70.7 nm, a high drug loading capacity (12.3%), and a superior photothermal conversion efficiency of 48.7%. The nanovaccine leverages the homologous targeting capacity of CCMs for precise tumor homing, while the disulfide-cross-linked CDCs enable glutathione-triggered drug release specifically within the tumor microenvironment for controlled chemotherapy. Under near-infrared laser irradiation, the CDCs generate robust photothermal ablation of primary tumors, and the combination of chemotherapy and photothermal therapy (PTT) effectively induces immunogenic cell death (ICD), which synergizes the self-adjuvant of CDCs and CCM antigens to generate significant antitumor response to suppress both primary and distant tumors in a bilateral NPC mouse model. In a prophylactic setting, the nanovaccine pre-vaccination generates effective immune protection against subsequent tumor challenge. This work provides a promising "full-cycle" nanoplatform that synergistically integrates PTT, chemotherapy, and immunotherapy for both NPC treatment and prophylaxis.
Dual-mode wearable patches usually stack discrete sensing and energy modules made from dissimilar materials, which increases thickness and limits skin conformability. Here we report a hydrogel iontronic patch, 1.56 mm thick, in which both pressure sensing and moisture-electric signaling arise from a single H3PO4/ZnCl2/poly(vinyl alcohol) hydrogel by tuning the ZnCl2-to-H3PO4 ratio. The two functional layers share one Zn foil as a common internal electrode, merging two device stacks into a single compact unit while keeping the channels electrically independent. The pressure-sensing layer delivers a sensitivity of up to 0.60 nF kPa-1 with a measurement range extending to 2 MPa with stable response across 10,000 cycles. The moisture-electric layer generates about 0.8 V at 90% relative humidity and remains stable for over 100 h. The pressure channel captures arterial pulse, respiration, and joint motion, while the moisture channel tracks breathing- and perspiration-related humidity. Coupled with a one-dimensional convolutional neural network, the multichannel pressure output recognizes five representative tennis strokes, with cross-subject validation on five additional volunteers achieving 92.8% mean accuracy, offering a material-level route toward thinner, skin-conformable wearable healthcare.
NAD(P)H is a critical redox cofactor in cellular energy metabolism, yet real-time monitoring of its spatiotemporal dynamics in pathological contexts remains challenging due to the limited penetration depth and resolution of conventional imaging modalities. In this study, we developed a dual-modal ratiometric imaging nanoprobe that enables precise photoacoustic (PA) and upconversion luminescence imaging of this energy metabolism substrates. The nanoprobe conjugates an NAD(P)H-responsive chromophore and an internal reference dye onto NIR-excited upconversion nanoparticles, enabling self-calibrated quantification through ratiometric UCL and mPAT signals. This design minimizes artifacts from nanoprobe distribution and environmental variations, enhancing spatiotemporal accuracy. The utility of the nanoprobe is demonstrated in multiple disease models: it visualizes metabolic reprogramming during macrophage M1 polarization, tracks aberrant NAD(P)H accumulation in drug-induced and acute liver injury (ALI), and monitors metabolic responses to NAC and 2-DG interventions. Furthermore, in a calorie restriction (CR) combined immunotherapy model, the nanoprobe reveals that the TLR7/8 agonist R848 and glycolytic inhibitor 2-DG synergistically suppress tumor growth by reprogramming tumor-associated macrophage metabolism. This work provides a robust imaging platform for tracking energy metabolism dynamics, offering insights into the interplay between metabolic pathways and inflammatory diseases for developing targeted therapies.
With the growth of the older adult population and the increasing incidence of traumatic injuries, the use of orthopedic devices has risen significantly. However, in addition to material-related limitations, one of the most serious challenges associated with these devices is the risk of infection. To address this issue, an innovative hydrogel is presented to prevent infection at the source during orthopedic surgery. This hydrogel combines polyhexamethylene biguanide (PHMB), a positively charged agent with proven broad-spectrum antimicrobial activity, with a thermosensitive polymer. The resulting formulation provides suitable viscosity for application or dip-coating onto orthopedic devices, thereby forming a stable physical and chemical barrier. The new hydrogel exhibits temperature-responsive viscosity, which enhances both adherence and controlled release at body temperature. Additionally, the hydrogel demonstrates antibacterial effectiveness against both Gram-positive and Gram-negative bacteria, along with low cytotoxicity, minimal immune response, and excellent anti-biofouling properties. These features make the developed hydrogel well suited for orthopedic surgical procedures and support its potential as a complementary approach to reducing the risk of postoperative infections.
Impaired blood-testis barrier (BTB) integrity, induced by oxidative stress, is one of the primary factors leading to spermatogenic disorders in cryptorchidism. Therefore, the targeted elimination of testicular oxidative stress and repair of the BTB are promising strategies for promoting spermatogenesis in patients with cryptorchidism. This study aimed to demonstrate the potential of Sertoli cell membrane-camouflaged biomimetic vesicles loaded with resveratrol carbon dots (RCD@PCy@EVs) as a therapeutic nanoagent for cryptorchidism treatment in vivo. The prepared RCD@PCy@EVs are actively targeted to the seminiferous tubules by leveraging the homing tendency of the Sertoli cell membrane, guided by fluorescence imaging. The RCD@PCy@EVs not only reshape the redox microenvironment of the seminiferous tubules and alleviate inflammatory responses by scavenging reactive oxygen species, but they also increase the expression of the tight junction protein β-catenin and restore BTB integrity, which is associated with the activation of the SIRT1/AMPKα/FOXO1 signaling pathway. More importantly, functional spermatogenesis is markedly improved by RCD@PCy@EVs, effectively restoring reproductive function in cryptorchid mice. The RCD@PCy@EVs-mediated therapy for cryptorchidism offers a novel strategy for treating male infertility.
Hydrogels have emerged as promising candidates for next-generation implantable biomedical stents. However, the scalable fabrication of hydrogel three-dimensional (3D) stents with sufficient mechanical support remains a major challenge, owing to the intrinsic flexibility of hydrogel materials. Here, inspired by the water-welding mechanism of the butterfly proboscis, we report a facile water-mediated welding strategy for sodium alginate (SA) films, which enables the assembly of fully integrated 3D stents using only water as the processing medium. The as-prepared solid-walled 3D stents can be seamlessly converted into hollow-walled architectures via a metal ion-induced asymmetric crosslinking followed by solvent exchange. Notably, the hollow-walled structure enables the mechanical support force five times that of solid-walled ones, rendering these hydrogel 3D stents highly attractive for biodegradable medical stents. This work provides a versatile and environmentally benign route to engineer 3D hydrogel stents, thereby advancing the development of advanced implantable biomedical devices.
The blood-brain barrier (BBB), while indispensable for maintaining central nervous system (CNS) homeostasis, constitutes the principal impediment to effective therapeutic delivery for neurodegenerative disorders, particularly hindering spatially resolved modulation of extracellular ions and reactive oxygen species (ROS) within the neural microenvironment. Contemporary electrochemical methodologies have emerged as a paradigm shift for dynamically reconciling these dual parameters, thereby enabling targeted neuroregulation. Critical review of this field reveals a distinct evolution from passive physiological interventions to active electrochemical engineering approaches. Current research, however, encounters persistent translational barriers including insufficient spatiotemporal resolution in neural interfaces, incomplete mechanistic understanding of ROS-ionic crosstalk, and scalability limitations of nanoscale delivery systems. To transcend these limitations, the synergistic convergence of electrochemical platforms with machine learning (ML)-guided predictive analytics, near-infrared (NIR) phototherapy, and biocompatible nanocarrier-mediated delivery systems constitutes a strategic imperative in next-generation neurotherapeutic development. Such interdisciplinary convergence is not merely incremental but rather a fundamental prerequisite for realizing clinically translatable neural microenvironment modulation.
Magnetically driven biofabrication is emerging as a materials-enabled extension of tissue engineering, integrating advances in magnetic nanoparticle (MNP) design with cells, spheroids, and biomaterial scaffolds to engineer responsive and remotely controllable living systems. Progress in nanoparticle engineering has yielded biocompatible and tunable MNP formulations that can be incorporated into hydrogels, spheroids, organoids, and scaffolds, where they influence cellular behavior, extracellular matrix organization, and mechanotransduction. Externally applied magnetic fields further enable non-contact control over cell positioning, microtissue assembly, matrix alignment, and dynamic mechanical stimulation, expanding the design space of 3D and 4D biofabrication. This Review critically maps and unifies the multiscale design principles underlying magnetically driven biofabrication, spanning nanoparticle design, magnetic actuation strategies, and biological responses. We compare approaches ranging from single-cell manipulation and magnetoactive bioinks to spheroid fusion and microfluidic systems with embedded magnetic actuation. We further discuss how physics-based modeling, data-informed optimization, and emerging digital twin concepts may help connect material properties, magnetic field design, and biological response. Finally, we examine translational considerations, including Good Manufacturing Practice (GMP)-compatible nanoparticle formulations, mechanistic clarity, long-term safety evaluation, and regulatory alignment, converging toward magnetically enabled tissue-engineered advanced therapy medicinal products (Mag-TE ATMPs).
Traditional hydrogel dressings face challenges like poor adhesion and limited antibacterial effects. We developed a biocompatible polyacrylamide-DNA double-network hydrogel (AuPt/PEDOT-DNA gel), cross-linked by bis-acrylamide and DNA duplexes, offering softness, stretchability, and self-adhesiveness for direct skin application. Incorporating AuPt/PEDOT, a cascade nanozyme with peroxidase/oxidase-mimicking activities and high photothermal efficiency, enables dual antibacterial action via ROS generation and photothermal therapy. Under near-infrared irradiation, it achieves > 95% bacterial killing at safe concentrations and inhibits biofilm formation. Moreover, the intrinsic conductivity of the AuPt/PEDOT-DNA gel enables its operation as a flexible strain sensor that transduces skin deformation into motion signals, which can be harnessed to monitor periwound mechanical strain and provide active feedback to prevent excessive tissue tension, thereby complementing the antimicrobial and drug-delivery functions with biomechanical protection during rehabilitation. It conforms to wounds, prevents drug leakage, and eradicates bacteria, enhancing prospects for advanced hydrogel dressings.
Secondary injury after traumatic brain injury (TBI) is characterized by excessive reactive oxygen species (ROS) production and persistent neuroinflammation, which remain difficult to control using a single therapeutic agent. Herein, a dissolvable microneedle platform based on Prussian blue (PB) nanoparticles was developed to locally deliver curcumin (Cur) or edaravone (EDA) into injured brain tissue through a transiently disrupted blood-brain barrier. The microneedles were fabricated from hyaluronic acid/carboxymethyl chitosan (HCMN) using a low-temperature multilayer drying process while maintaining the structural integrity of PB nanoparticles. Acting as both ROS-scavenging nanozymes and drug carriers, PB nanoparticles enabled flexible incorporation of different therapeutic agents within the same delivery platform. In vitro and in vivo studies showed that HCMN/PB/Cur exhibited greater anti-inflammatory activity under relatively mild pathological conditions, whereas HCMN/PB/EDA displayed stronger antioxidant capacity under higher oxidative stress. These results suggest that different therapeutic formulations may be preferable under distinct pathological conditions while preserving the same delivery platform. This microneedle system provides a localized delivery approach and offers greater flexibility for formulation selection in the treatment of acute TBI.
Osteoporotic fractures pose a significant clinical challenge in aging societies due to the limited efficacy and high re-fracture risk associated with conventional treatments. To address this, we developed EXOs@ECM-SCS, a multifunctional bioactive hydrogel that encapsulates exosomes derived from induced pluripotent stem cell-induced mesenchymal stem cells within a hybrid matrix of decellularized extracellular matrix and methacrylated sulfated chitosan. This composite system promotes bone regeneration through a synergistic strategy that concurrently targets angiogenesis, immunomodulation, neurogenesis, and osteogenesis (AINO). Experimental results demonstrated that EXOs@ECM-SCS significantly enhanced osteogenic differentiation, angiogenic activity, and neural regeneration, while also driving macrophage polarization toward the M2 phenotype. These multifaceted effects collectively improved bone mass accumulation, mineralization, and fracture healing in an osteoporotic mouse model. Mechanistic insights from exosomal sequencing highlighted the involvement of key miRNAs such as miR-100-5p and miR-320a-3p, along with PI3K-Akt and MAPK signaling pathways. These findings underscore EXOs@ECM-SCS as an innovative therapeutic platform that leverages coordinated multimodal regulation to accelerate osteoporotic fracture repair.
Prostate cancer (PCa) is the most prevalent malignancy in men, often progressing to a more refractory form castration-resistant prostate cancer (CRPC) after primary androgen deprivation therapy. Immunotherapy has brought new hope to PCa patients, but the immunosuppressive characteristics of PCa cells limit its efficacy. Cuproptosis, which can affect tumorigenesis, therapeutic resistance, and immune modulation has received significant attention recently. However, it is limited by insufficient copper ion (Cu2+) concentration, hypoxia, and overexpression of glutathione (GSH) in tumors. To overcome these limitations, a targeted nanoplatform (CuS@MYC-PEG-FA) is fabricated to achieve a synergistic cuproptosis and immunotherapy. CuS@MYC-PEG-FA can not only promote reactive oxygen species (ROS) generation and Cu2+ release, but also elicit a powerful antitumor immunity response. Meanwhile, the loaded c-MYC inhibitor (MYCMI-6) can reduce the expression of glutaminase and subsequently inhibit the generation of GSH, further sensitizing cells to cuproptosis effectively. Notably, cuproptosis combined with photothermal therapy (PTT) can turn the "cold" tumor properties of PCa into "hot" ones, leading to its sensitivity to anti-programmed death ligand 1 (anti-PD-L1) immunotherapy. The results show that the combination of CuS@MYC-PEG-FA and PD-L1 inhibitor treatment can significantly inhibit the development of PCa, providing a new strategy for the treatment of PCa.
