A Triple Therapeutic Strategy with Antiexosomal Iron Efflux for Enhanced Ferroptosis Therapy and Immunotherapy.

Ferroptosis is a form of regulated cell death which can not only kill tumor cells but also enhance immunogenicity of tumor cells, and it is evidenced to be involved in a variety of tumor treatments, especially in cancer immunotherapy. Tumor cell-derived exosomes are reported to influence the progression and metastasis process of tumors. In the process of ferroptosis, exosomes are also demonstrated as mediators to export iron under high intracellular iron concentration and resist ferroptosis. Under this regard, the combined application of ferroptosis inducer and the inhibitor of iron-containing exosomes may enhance the ferroptosis. Herein, biocompatible hybrid nanoparticles composed of the iron oxide nanoparticles, polymers with oxaliplatin attached, and siProminin2 are constructed. The siProminin2 mediated exosomal inhibition can restore the intracellular iron concentration, which can also inhibit the secretion of tumor cell-derived exosomes. The combination of immunotherapy with oxaliplatin, ferroptosis-based cancer therapy and inhibition of tumor cell-derived exosomes can enhance the immune activation effects. The nanoparticles represent an excellent triple therapeutic strategy for enhancing ferroptosis-based cancer therapy and immunotherapy.

ROS/Electro Dual-Reactive Nanogel for Targeting Epileptic Foci to Remodel Aberrant Circuits and Inflammatory Microenvironment.

Medicinal treatment against epilepsy is faced with intractable problems, especially epileptogenesis that cannot be blocked by clinical antiepileptic drugs (AEDs) during the latency of epilepsy. Abnormal circuits of neurons interact with the inflammatory microenvironment of glial cells in epileptic foci, resulting in recurrent seizures and refractory epilepsy. Herein, we have selected phenytoin (PHT) as a model drug to derive a ROS-responsive and consuming prodrug, which is combined with an electro-responsive group (sulfonate sodium, SS) and an epileptic focus-recognizing group (α-methyl-l-tryptophan, AMT) to form hydrogel nanoparticles (i.e., a nanogel). The nanogel will target epileptic foci, release PHT in response to a high concentration of reactive oxygen species (ROS) in the microenvironment, and inhibit overexcited circuits. Meanwhile, with the clearance of ROS, the nanogel can also reduce oxidative stress and alleviate microenvironment inflammation. Thus, a synergistic regulation of epileptic lesions will be achieved. Our nanogel is expected to provide a more comprehensive strategy for antiepileptic treatment.

20(R)-ginsenoside Rg3-loaded polyurethane/marine polysaccharide based nanofiber dressings improved burn wound healing potentials.

The management of deep burn injuries is extremely challenging, ascribed to their delayed wound healing rate, susceptibility for bacterial infections, pain, and increased risk of hypertrophic scarring. In our current investigation, a series of composite nanofiber dressings (NFDs) based on polyurethane (PU) and marine polysaccharides (i.e., hydroxypropyl trimethyl ammonium chloride chitosan, HACC and sodium alginate, SA) were accomplished by electrospinning and freeze-drying protocols. The 20(R)-ginsenoside Rg3 (Rg3) was further loaded into these NFDs to inhibit the formation of excessive wound scars. The PU/HACC/SA/Rg3 dressings showed a sandwich-like structure. The Rg3 was encapsulated in the middle layers of these NFDs and slowly released over 30 days. The PU/HACC/SA and PU/HACC/SA/Rg3 composite dressings demonstrated superior wound healing potentials over other NFDs. These dressings also displayed favorable cytocompatibility with keratinocytes and fibroblasts and could dramatically accelerate epidermal wound closure rate following 21 days of the treatment of a deep burn wound animal model. Interestingly, the PU/HACC/SA/Rg3 obviously reduced the excessive scar formation, with a collagen type I/III ratio closer to the normal skin. Overall, this study represented PU/HACC/SA/Rg3 as a promising multifunctional wound dressing, which promoted the regeneration of burn skins and attenuated scar formation.

Sustainable Antibacterial and Anti-Inflammatory Silk Suture with Surface Modification of Combined-Therapy Drugs for Surgical Site Infection.

Silk sutures with antibacterial and anti-inflammatory functions were developed for sustained dual-drug delivery to prevent surgical site infections (SSIs). The silk sutures were prepared with core-shell structures braided from degummed silk filaments and then coated with a silk fibroin (SF) layer loaded with berberine (BB) and artemisinin (ART). Both the rapid release of drugs to prevent initial biofilm formation and the following sustained release to maintain effective concentrations for more than 42 days were demonstrated. In vitro assays using human fibroblasts (Hs 865.Sk) demonstrated cell proliferation on the materials, and hemolysis was 2.4 ± 0.8%, lower than that required by ISO 10993-4 standard. The sutures inhibited platelet adhesion and promoted collagen deposition and blood vessel formation. In vivo assessments using Sprague-Dawley (SD) rats indicated that the coating reduced the expression of pro-inflammatory cytokines interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α), shortening the inflammatory period and promoting angiogenesis. The results demonstrated that these new sutures exhibited stable structures, favorable biocompatibility, and sustainable antibacterial and anti-inflammatory functions with potential for surgical applications.

Propionate and butyrate attenuate macrophage pyroptosis and osteoclastogenesis induced by CoCrMo alloy particles.

BACKGROUND: Wear particles-induced osteolysis is a major long-term complication after total joint arthroplasty. Up to now, there is no effective treatment for wear particles-induced osteolysis except for the revision surgery, which is a heavy psychological and economic burden to patients. A metabolite of gut microbiota, short chain fatty acids (SCFAs), has been reported to be beneficial for many chronic inflammatory diseases. This study aimed to investigate the therapeutic effect of SCFAs on osteolysis. METHODS: A model of inflammatory osteolysis was established by applying CoCrMo alloy particles to mouse calvarium. After two weeks of intervention, the anti-inflammatory effects of SCFAs on wear particle-induced osteolysis were evaluated by Micro-CT analysis and immunohistochemistry staining. In vitro study, lipopolysaccharide (LPS) primed bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) macrophages were stimulated with CoCrMo particles to activate inflammasome in the presence of acetate (C2), propionate (C3), and butyrate (C4). Western blotting, Enzyme-linked immunosorbent assay, and immunofluorescence were used to detect the activation of NLRP3 inflammasome. The effects of SCFAs on osteoclasts were evaluate by qRT-PCR, Western blotting, immunofluorescence, and tartrate-resistant acid phosphatase (TRAP) staining. Additionally, histone deacetylase (HDAC) inhibitors, agonists of GPR41, GPR43, and GPR109A were applied to confirm the underlying mechanism of SCFAs on the inflammasome activation of macrophages and osteoclastogenesis. RESULTS: C3 and C4 but not C2 could alleviate wear particles-induced osteolysis with fewer bone erosion pits (P < 0.001), higher level of bone volume to tissue volume (BV/TV, P < 0.001), bone mineral density (BMD, P < 0.001), and a lower total porosity (P < 0.001). C3 and C4 prevented CoCrMo alloy particles-induced ASC speck formation and nucleation-induced oligomerization, suppressing the cleavage of caspase-1 (P < 0.05) and IL-1ß (P < 0.05) stimulated by CoCrMo alloy particles. C3 and C4 also inhibited the generation of Gasdermin D-N-terminal fragment (GSDMD-NT) to regulate pyroptosis. Besides, C3 and C4 have a negative impact on osteoclast differentiation (P < 0.05) and its function (P < 0.05), affecting the podosome arrangement and morphologically normal podosome belts formation. CONCLUSION: Our work showed that C3 and C4 are qualified candidates for the treatment of wear particle-induced osteolysis.

Click-Nucleic-Acid-Containing Codelivery System Inducing Collapse of Cellular Homeostasis for Tumor Therapy through Bidirectional Regulation of Autophagy and Glycolysis.

As a rapid proliferating tissue, tumor cells have to optimize nutrient utilization to withstand harsh conditions. Several approaches have been explored to inhibit the growth and metastasis of tumor by disrupting the reprogrammed tumor metabolism. However, nutrient limitations within solid tumors may induce the metabolic flexibility of malignant cells to sustain growth and survival using one nutrient to fill metabolite pools normally supplied by the other. To overcome this predicament, a promising click-nucleic-acid-containing platform for codelivery of rapamycin, anti-PFKFB4 siRNA, and targeting ligand aptamer AS1411 was applied. PFKFB4 could act as a promising target for tumor therapy for being a molecular fulcrum that could couple glycolysis to autophagy by promoting aggressive metastatic tumors. The downregulation of PFKFB4 can help inhibit the SRC3/Akt/mTOR pathway, leading autophagy to the direction of promoting apoptosis of tumor cells, which is induced by the collapse of tumor cellular homeostasis, while low dosages of rapamycin could decrease surgery-induced immune dysfunction. Enhanced tumor autophagy, favorable in vivo antitumor efficacy, and effective systematic immune activation are observed after treatment, suggesting that autophagy and glycolysis can serve as an integrated target for tumor treatment.

Microthrombus-Targeting Micelles for Neurovascular Remodeling and Enhanced Microcirculatory Perfusion in Acute Ischemic Stroke.

Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self-assembled micelles that are consisted of reactive oxygen species (ROS)-responsive and fibrin-binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood-brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.