Advanced Healthcare Materials最新文献

Recent advancements in photodynamic therapy (PDT) have highlighted its potential as a non-invasive cancer treatment. However, to fully realize the clinical potential of PDT, the development of innovative photosensitizers is essential. In this study, efficient heavy-atom-free PSs (IR820-1-3) activated by 808 nm light irradiation were developed by incorporating electron-rich/sterically bulky groups at the meso-position of the IR820 scaffold, a novel indocyanine green derivative. Notably, experimental results and transient absorption spectroscopic studies indicated that substituent bulkiness plays a key role in promoting reactive oxygen species (ROS) generation. IR820-3 PS, with a highly twisted molecular structure, demonstrated superior ROS production via both type I and type II photochemical pathways. The self-assembled nanostructure of IR820-3 underwent partial disassembly upon interaction with albumin, resulting in enhanced fluorescence intensity and photodynamic efficiency. Interestingly, the cationic cyanine backbone facilitated the mitochondria-specific localization of IR820-3, which further contributed to IR820-3's effective PDT performance against cancer cells. Importantly, in vivo findings indicated that the IR820-3 exhibited excellent tumor-targeting ability and induced efficient tumor photoablation under 808 nm NIR irradiation. This study provides insights into the molecular design of a facile, "one-for-all" NIR photosensitizer based on a heptamethine cyanine platform, highlighting its potential for preclinical and clinical applications.

Sickle cell disease (SCD), a monogenic disorder arising from a single point mutation in the β-globin gene, continues to pose a significant global health burden despite advances in supportive care. This mutation drives the formation of hemoglobin S (HbS) polymers under deoxygenated conditions, causing erythrocyte sickling, vaso-occlusive crises, and multi-organ complications. Current therapies, such as hydroxyurea and voxelotor, provide only partial symptomatic relief, underscoring the urgent need for transformative strategies. This review highlights the molecular glue paradigm, a novel approach that repurposes hemoglobin itself as a therapeutic scaffold. By integrating high-resolution structural insights from cryo-electron microscopy and predictive modeling via artificial intelligence, engineered hemoglobin variants can be rationally designed to inhibit polymerization, stabilizing non-pathogenic conformations and preventing fiber formation. These molecular glues, generated through gene editing or synthetic biology, offer a cell-intrinsic, high-concentration mechanism to counteract HbS polymerization, potentially overcoming the limitations of current therapies. We examine the key challenges in translating this paradigm, including precise structural characterization of polymerization intermediates, efficient intracellular delivery to erythrocytes, temporal regulation under hypoxic conditions, and the mitigation of immunogenicity.

Rejection following heart transplantation remains a significant challenge in the medical science. In addition to the immune response, the inflammatory response and microvascular endothelial damage can exacerbate rejection; however, current therapies focus primarily on the immune response. Numerous studies have confirmed that miR-126 regulates vascular inflammation and promotes angiogenesis. To achieve the precise targeted delivery of miR-126, macrophage biomimetic ultrasound phase-change cationic nanoparticles carrying miR-126 (miR-126-MCNPs) are synthesized. Incorporation of the macrophage membrane enhances the anti-phagocytic and inflammatory targeting of nanoparticles, thereby prolonging the circulation time and promoting aggregation in the transplanted heart. Using ultrasound-targeted microbubble destruction (UTMD), the perfluoropentane nanoparticle core undergoes a phase change in the ultrasound irradiation zone, allowing the targeted delivery of macrophage membranes and miR-126, and significantly improving the transfection efficiency of the miR-126. Consequently, anti-inflammatory effects are achieved, such as inhibition of macrophage and CD3⁺ T cells infiltration, and alteration of M2-type macrophage differentiation. In addition, this study demonstrates that the combination of miR-126-MCNPs with UTMD can alleviate the extent of vascular endothelial and interstitial fibrosis in transplanted hearts, increase angiogenesis, and improve microcirculation and cardiac function. This research provides a new strategy for the precision-targeted therapy of cardiac transplant rejection.

Ovarian cancer (OvCa) remains a leading cause of gynecological cancer mortality, particularly due to its aggressive peritoneal metastasis. Conventional treatments, including surgery and paclitaxel-based chemotherapy, are often limited by poor drug penetration into solid tumors, multidrug resistance, and the highly immunosuppressive tumor microenvironment. To overcome these challenges, we engineered a novel bacteria membrane-fused biomimetic paclitaxel liposome (PLip@DMV) by incorporating bacteria membrane-derived vesicles from attenuated Salmonella VNP20009. Administered via intraperitoneal injection, PLip@DMV not only delivered paclitaxel effectively but also leveraged the immunomodulatory properties of the Salmonella membrane. This led to significant antitumor immune activation within the metastatic tumor microenvironment, synergistically enhancing therapeutic efficacy and markedly prolonging the survival of tumor-bearing mice. Furthermore, the enhanced delivery efficiency and sustained-release characteristics of PLip@DMV resulted in significantly reduced systemic toxicity and tissue accumulation compared to free paclitaxel. Our findings demonstrate that PLip@DMV represents a more efficient, safer, and immunologically potentiated strategy for treating peritoneal metastatic ovarian cancer. This novel biomimetic nanocarrier holds significant promise for improving clinical outcomes in advanced OvCa.

Impaired diabetic wound healing is driven by immune dysregulation and microenvironmental disruptions induced by hyperglycemia, leading to excessive inflammation and defective macrophage polarization. Although macrophage extracellular traps (METs) play critical roles in chronic inflammatory diseases, their involvement in shaping the diabetic wound immune microenvironment and impeding macrophage polarization remains insufficiently understood. Here, we present zinc-containing bioactive glass (ZnBG), in which zinc incorporation confers immunomodulatory properties. In a type 2 diabetic full-thickness skin excision model, ZnBG significantly mitigates MET-associated oxidative stress and inflammation. Mechanistic investigations reveal that ZnBG effectively suppresses MET formation by reducing reactive oxygen species levels, inhibiting PAD4 activation, and blocking the NLRP3/caspase-1/GSDMD signaling pathway. Consequently, ZnBG facilitates macrophage transition from the pro-inflammatory M1 phenotype to the reparative M2 phenotype in diabetic wounds, thereby alleviating inflammation, enhancing neovascularization, and ultimately promoting diabetic wound healing. These findings provide an innovative therapeutic strategy that integrates ZnBG with targeted modulation of macrophage function for the treatment of diabetic wounds.

Effective resource-constrained volumetric ultrasound imaging requires compact, low-power systems capable of wide-angle real-time 3D imaging to accommodate small changes in placement by the operator. However, obtaining such images requires an excessive O(N²) channel count, bulky electronics, and high power consumption. We introduce an end-to-end system architecture to enable high-resolution, real-time 3D ultrasound imaging in a portable form factor. We present: a convolutional optimally distributed array (CODA) geometry that drastically reduces the number of elements (from 1024 to 128), a novel chirped data acquisition (cDAQ) architecture that enhances imaging depth while operating with a 25.3 dB lower transmit amplitude than a pulsed system, and an associated new signal processing methodology. We experimentally demonstrate our system's ability to perform deep (> 11 cm), high axial resolution (< 600 µm), and wide-angle (57°) imaging, while simultaneously reducing power consumption (29.6x reduction) and drive voltage (18 V). We validated our system in vitro and further performed in vivo human trials, demonstrating the ability to detect both tumors and cysts in breast tissue. This new architectural approach will unlock a new class of medical devices with enhanced diagnostic and long-term monitoring capabilities and open up future wearable designs of real-time 3D ultrasound systems.

Therapeutic siRNA application is limited by its endosomal entrapment and subsequent degradation. Here, we rationally develop a dual-pathway polymeric carrier, PFCPD, by co-assembling two functional cell-penetrating poly(disulfide)s (CPDs): PCPD, bearing a photosensitizer, and FCPD, modified with a folate-targeting ligand. This hybrid design enables efficient siRNA delivery by combining thiol-mediated membrane penetration, which facilitates direct cytosolic transport via disulfide exchange at the cell surface, and photochemical internalization (PCI), allowing endocytosed complexes to escape from endo/lysosomes upon light-triggered reactive oxygen species (ROS) generation. Simultaneously, intracellular glutathione (GSH) cleaves the polymer backbone to release siRNA and is consumed in the process, sensitizing cells to oxidative damage. When loaded with anti-GPX4 siRNA (siGPX4), PFCPD induces potent ferroptosis by downregulating GPX4 and amplifying ROS stress under illumination. The combination of ferroptosis and type I photodynamic therapy synergistically triggers immunogenic cell death, promotes dendritic cell maturation, and activates CD8⁺ T cell-mediated antitumor immunity in bilateral tumor models. This work presents a CPD-based siRNA nanoplatform that uniquely integrates thiol-mediated cytosolic entry with PCI-assisted endosomal escape in a single system, addressing the trade-off between tumor targeting and cytosolic accessibility. It offers a versatile strategy for siRNA delivery capable of achieving efficient cancer therapy.

The inflammatory cascade initiated by acute spinal cord injury (SCI) is a crucial element contributing to subsequent pathological damage. Uncontrolled or excessive inflammatory responses aggravate neural tissue destruction and hinder the regenerative process. Stimulator of interferons genes (STING) is a key regulator in the innate immune signaling pathway that promotes the generation of inflammatory mediators by activating the TBK1 and IRF3 signaling pathways, thereby shaping the post-injury microenvironment. In this study, we developed a hyaluronic acid-phenylboronic acid-polyvinyl alcohol-based hydrogel (HA-PBA-PVA, termed HPP) as a local delivery vehicle for the STING-specific inhibitor C-176, which was applied directly to the injury epicenter in a rat model of complete spinal cord transection. The locally implanted C-176@HPP can effectively deliver C-176 to the injured site, markedly reducing the expression of pro-inflammatory cytokines by regulating the STING/TBK1 signaling pathway. Moreover, the administration of C-176@HPP can significantly attenuate microglial activation and promote neuronal survival and axonal regeneration, which eventually contribute to locomotor improvement after SCI. Our findings demonstrate that C-176@HPP provides a promising strategy for ameliorating neuro-inflammation and facilitating neural tissue regeneration after SCI.

Fibroblast-mediated decreased collagen synthesis is a key aspect of skin aging. Polyhydroxyalkanoate (PHA) materials have established clinical biocompatibility; however, the direct mechanisms of PHA microspheres on fibroblast-mediated skin rejuvenation remain unexplored. We aimed to investigate the impact of PHA microspheres on collagen production and its underlying molecular pathways. The microspheres demonstrated high biocompatibility, promoting human fibroblast proliferation in vitro and showing robust systemic safety in a rat model. In vivo, PHA microsphere injection significantly increased epidermal thickness and the expression of collagen I and III. Mechanistically, PHA microspheres improved mitochondrial function, as evidenced by elevated ATP production. MYBL2 was identified as a key transcriptional regulator; its knockdown attenuated fibroblast proliferation, collagen synthesis, and mitochondrial function. Importantly, PHA stimulation failed to rescue this effect, confirming that MYBL2 is required for the observed regeneration. In summary, we demonstrate that PHA microspheres drive fibroblast proliferation and collagen synthesis by upregulating MYBL2 and enhancing mitochondrial function. These findings provide a theoretical basis for the application of PHA microspheres as a collagen stimulant for skin rejuvenation.

Thrombosis and inflammation, the primary causes of blood-contacting medical device failure, are initiated by interfacial biofouling. Although zwitterionic hydrogel coatings represent a promising solution, their clinical translation is hampered by the formidable challenge of simultaneously integrating mechanical robustness, high-strength substrate adhesion, and exceptional antifouling properties. Herein, we report a bioinspired zwitterionic hydrogel coating that overcomes this hurdle through a design combining microstructural alignment with multi-site chemical anchoring. The coating leverages cellulose nanocrystals (CNC) to induce an aligned microstructure that enhances antifouling through modulated interfacial hydrodynamics, while providing structural reinforcement for superior mechanical stability. An in situ multi-site chemical anchoring strategy is developed, enabling the coating to achieve an interfacial adhesion energy exceeding 800 J/m² on PVC substrates. Inspired by the vascular endothelium, the microstructure-aligned zwitterionic hydrogel coating significantly inhibits protein adsorption, platelet adhesion, and bacterial colonization. It retains outstanding stability even after 42 days of PBS shearing, 200 cycles of sandpaper abrasion, and 30 min of high-speed water flushing. Crucially, the coated PVC prevents biofilm formation and mitigates the foreign body response, while also inhibiting thrombus formation in an anticoagulant-free ex vivo rabbit circulatory model. This work lays the foundation for designing next-generation hemocompatible coatings for medical devices.