Advanced Healthcare Materials最新文献

Glioblastoma (GBM) is a highly aggressive brain tumor known for its resistance to standard treatments. Despite surgery being a primary option, it often leads to incomplete removal and high recurrence rates. Photodynamic therapy (PDT) holds promise as an adjunctive treatment, but safety concerns and the need for high-power lasers have limited its widespread use. This research addresses these challenges by introducing a novel PDT approach, using chlorin e6 (Ce6) enclosed in nanostructured lipid carriers (Ang-Ce6-NLCs) and targeted to GBM with the angiopep-2 peptide. Remarkably, a single 5-min irradiation session with LEDs at 660 nm and low power density (10 mW cm^{- 2}) proves effective against GBM, while reducing safety risks associated with high-power lasers. Encapsulation improves Ce6 stability and performance in physiological environments, while angiopep-2 targeting enhances delivery to GBM cells, maximizing treatment efficacy and minimizing off-target effects. The findings demonstrate that Ang-Ce6-NLCs-mediated PDT brings about a significant reduction in GBM cell viability, increases oxidative stress, reduces tumor migration, and enhances apoptosis. Overall, such treatment holds potential as a safe and efficient intraoperative removal of GBM infiltrating cells that cannot be reached by surgery, using low-power LED light to minimize harm to surrounding healthy tissue while maximizing tumor treatment.

Critical-size bone trauma injuries present a significant clinical challenge because of the limited availability of autografts. In this study, a photocurable composite comprising of polycaprolactone, polypropylene fumarate, and nano-hydroxyapatite (nHAP) (P─P─H) is printed, which shows good osteoconduction in a rat model. A cryogel composed of gelatin-nHAP (GH) is developed to incorporate osteogenic components, specifically bone morphogenetic protein-2 (BMP-2) and zoledronic acid (ZA), termed as GH+B+Z, which is investigated for osteoinductive property in a rat model. Further, a 3D-printed P─P─H scaffold impregnated with GH+B+Z is designed and implanted in a critical-size defect (25 × 10 × 5 mm) in goat tibia. After 4 months, the scaffold is well-integrated with adjacent native bone, with osteoinduction observed in the cryogel-filled region and osteoconduction over the printed scaffold. X-ray radiography and micro-CT analysis showed bone in-growth in the treatment group with 45 ± 1.4% bone volume/tissue volume (BV/TV), while the defect remained unhealed in the control group with BV/TV of 10.5 ± 0.5%. Histology showed significant cell infiltration and matrix deposition over the printed P─P─H scaffold and within the GH cryogel site in the treatment group. Immunohistochemical staining depicted significantly higher normalized collagen I intensity in the treatment group (34.45 ± 2.61%) compared to the control group (4.22 ± 0.78).

Large segmental bone defects often lead to nonunion and dysfunction, posing a significant challenge for clinicians. Inspired by the intrinsic bone defect repair logic of "vascularization and then osteogenesis", this study originally reports a smart implantable hydrogel (PDS-DC) with high mechanical properties, controllable scaffold degradation, and timing drug release that can proactively match different bone healing cycles to efficiently promote bone regeneration. The main scaffold of PDS-DC consists of polyacrylamide, polydopamine, and silk fibroin, which endows it with superior interfacial adhesion, structural toughness, and mechanical stiffness. In particular, the adjustment of scaffold cross-linking agent mixing ratio can effectively regulate the in vivo degradation rate of PDS-DC and intelligently satisfy the requirements of different bone defect healing cycles. Ultimately, PDS hydrogel loaded with free desferrioxamine (DFO) and CaCO₃ mineralized ZIF-90 loaded bone morphogenetic protein-2 (BMP-2) to stimulate efficient angiogenesis and osteogenesis. Notably, DFO is released rapidly by free diffusion, whereas BMP-2 is released slowly by pH-dependent layer-by-layer disintegration, resulting in a significant difference in release time, thus matching the intrinsic logic of bone defect repair. In vivo and in vitro results confirm that PDS-DC can effectively realize high-quality bone generation and intelligently regulate to adapt to different demands of bone defects.

The immunosuppressive microenvironment severely limits the responsiveness of colorectal cancer (CRC) to immunotherapy. Herein, a pH and reactive oxygen species (ROS) dual-responsive autocatalytic release system (TPDM/PGA) is constructed to reverse the immunosuppressive microenvironment and potentiate CRC immunotherapy. Dihydroartemisinin (DHA) and mitoxantrone (MTO) are conjugated to ROS-responsive polyethylenimine (TP) via a ROS-cleavable linker, respectively, and then coated with polyglutamic acid (PGA) to endow pH and ROS dual-responsiveness. The dissociation of PGA within the acidic TME facilitates its deep penetration and cell internalization, while the intracellular released DHA and MTO in response to high levels of H₂O₂ further produced a large amount of ROS, forming positive feedback to accelerate drug release and exacerbate oxidative stress. TPDM/PGA collaboratively reversed the immunosuppressive microenvironment and induced a strong anti-tumor immune response when combined with anti-PD-L1 antibody, significantly inhibiting tumor growth and prolonging the survival time of CT26 and MC38 tumor-bearing mice. The excellent therapeutic effect, together with the good tolerance, make TPDM/PGA a promising candidate for enhanced immunotherapy of colorectal cancer.

Persistent luminescence nanoparticles (PLNPs) can achieve autofluorescence-free afterglow imaging, while near-infrared (NIR) emission realizes deep tissue imaging. Nanozymes integrate the merits of nanomaterials and enzyme-mimicking activities with simple preparation. Here PLNPs are prepared of Zn_1.2Ga_1.6Ge_0.2O₄:Cr_0.0075 with NIR emission at 700 nm. The PLNPs are then incubated with IrCl₃ solution, and the nanoparticles are collected and annealed at 750 °C to obtain iridium@PLNPs. Iridium is observed on the PLNPs at the atomic level as a single-atom nanozyme with peroxidase-like catalytic activity, photothermal conversion, and computed tomography (CT) contrast capability. After coating with exosome membrane (EM), the Ir@PLNPs@EM composite exhibits long-lasting NIR luminescence, peroxidase-like catalytic activity, photothermal conversion, and CT contrast capability, with the targeting capability and biocompatibility from EM. Thus, NIR afterglow/photothermal/CT trimodal imaging-guided photothermal-chemodynamic combination therapy is realized as validated with the in vitro and in vivo inhibition of tumor growth, while toxicity and side effects are avoided as drug-free treatment. This work offers a promising avenue for advanced single-atom nanozyme@PLNPs to promote the development of nanozymes and PLNPs for clinical applications.

Nicotinamide adenine dinucleotide (NADH) oxidase (NOX) is key in converting NADH to NAD⁺, crucial for various biochemical pathways. However, natural NOXs are costly and unstable. NOX nanozymes offer a promising alternative with potential applications in bio-sensing, antibacterial treatments, anti-aging, and anticancer therapies. This review provides a comprehensive overview of the types, functional mechanisms, biomedical applications, and future research perspectives of NOX nanozymes. It also addresses the primary challenges and future directions in the research and development of NOX nanozymes, underscoring the critical need for continued investigation in this promising area. These challenges include optimizing the catalytic efficiency, ensuring biocompatibility, and achieving targeted delivery and controlled activity within biological systems. Additionally, the exploration of novel materials and hybrid structures holds great potential for enhancing the functional capabilities of NOX nanozymes. Future research directions can involve integrating advanced computational modeling with experimental techniques to better understand the underlying mechanisms and to design more effective nanozyme candidates. Collaborative efforts across disciplines such as nanotechnology, biochemistry, and medicine will be essential to unlock the full potential of NOX nanozymes in future biomedical applications.

The challenges of multi-pathway immune resistance and systemic toxicity caused by the direct injection of immune checkpoint inhibitors are critical factors that compromise the effectiveness of clinical immune checkpoint blockade therapy. In this context, natural polyphenols have been employed as the primary component to construct a targeted and acid-responsive PD-L1 antibody (αPD-L1) delivery nanoplatform. This platform incorporates garcinol, an inhibitor of the Nuclear Factor Kappa-B (NF-κB) signaling pathway, to regulate pro-tumor immune escape cytokines and regulatory T cells. Additionally, the nanoplatform has been verified to induce immunogenic cell death (ICD), which promotes the maturation of dendritic cells and enhances the activity of cytotoxic T lymphocytes. In vivo and in vitro experimental results demonstrated that the nanoplatform can boost the immune response through a PD-L1 and NF-κB blocking/ICD inducing three-pronged strategy, thereby effectively combating tumor growth and metastasis.

Combination therapy based on precise phototherapies combined with immune modulation provides successful antitumor effects. In this study, a combination therapy is designed based on phototactic, photosynthetic, and phototherapeutic Chlamydomonas Reinhardtii (CHL)-glycol chitosan (GCS)-polypyrrole (PPy) nanoparticle (NP)-enhanced immunity combined with the tumor microenvironment turnover of cytotoxic T cells and M1/M2 macrophages, which is based on photothermal GCS-PPy NPs decorated onto the phototactic and photosynthetic CHL. Phototherapy based on CHL-GCS-PPy NPs alleviates hypoxia and modulates the tumor immune microenvironment, which induces tumor cell death. In particular, the precise antitumor immune response and potent immune memory induced by combining self-navigated phototherapies significantly alleviate the progression of bladder cancer in C57BL/6 mice and effectively inhibit bladder tumor growth. Furthermore, they also potentially prevent tumor recurrence, which provides a promising therapeutic strategy for clinical tumor therapy.

Pro-energetic effects of functionalized, oxidized carbon nanozymes (OCNs) are reported. OCNs, derived from harsh acid oxidation of single-wall carbon nanotubes or activated charcoal are previously shown to possess multiple nanozymatic activities including mimicking superoxide dismutase and catalyzing the oxidation of reduced nicotinamide adenine dinucleotide (NADH) to NAD⁺. These actions are predicted to generate a glycolytic shift and enhance mitochondrial energetics under impaired conditions. Impaired mitochondrial energy metabolism is increasingly recognized as an important facet of traumatic brain injury (TBI) pathophysiology and decreases the efficiency of electron transport chain (ETC)-coupled adenosine triphosphate (ATP) and NAD⁺ regeneration. In vitro, OCNs promote a pro-aerobic shift in energy metabolism that persists through ETC inhibition and enhances glycolytic flux, glycolytic ATP production, and cellular generation of lactate, a crucial auxiliary substrate for energy metabolism. To address specific mechanisms of iron injury from hemorrhage, OCNs with the iron chelator, deferoxamine (DEF), covalently-linked were synthesized. DEF-linked OCNs induce a glycolytic shift in-vitro and in-vivo in tissue sections from a rat model of TBI complicated by hemorrhagic contusion. OCNs further reduced hemorrhage volumes 3 days following TBI. These results suggest OCNs are promising as pleiotropic mediators of cell and tissue resilience to injury.

Pancreatic ductal adenocarcinoma (PDAC) relies heavily on neoangiogenesis for its progression, making early detection crucial. Here, LTZi-MHI148 (Letrozole inhibitor bonding with MHI-148 dye), a near-infrared (NIR) fluorescent agent is developed, to target RhoJ (Ras Homolog Family Member J), a protein expressed in neonatal vasculature, for both imaging and therapy of early PDAC. This agent is synthesized by conjugating Letrozole with MHI-148, exhibiting excellent NIR characteristics and photostability. In vitro studies showed that LTZi-MHI148 selectively accumulated within pancreatic cancer cells through Organic Anion Transporting Polypeptide (OATP) transporters and bound to cytoplasmic RhoJ. In vivo, the probe effectively targeted neoangiogenesis and Pancreatic Intraepithelial Neoplasias (PanINs) in various PDAC models, including the orthotopic, ectopic, spontaneous, and tamoxifen-induced tumors. Notably, LTZi-MHI148 detected preneoplastic PanIN lesions with Overexpressed RhoJ and active neoangiogenesis in both spontaneous and tamoxifen-induced PDAC murine models. Longitudinal imaging studies revealed that RhoJ-targeted neoangiogenesis tracks lesion progression, highlighting LTZi-MHI148's utility in monitoring disease progression. Furthermore, multiple LTZi-MHI148 administrations attenuated PanINs to PDAC progression, suggesting its potential as a therapeutic intervention. These findings underscore the translational potential of LTZi-MHI148 for the early detection and targeted therapy of PDAC, utilizing NIR-I/II imaging to monitor RhoJ overexpression in precancerous ductal neoplasia associated with neoangiogenesis.