International Journal of Nanomedicine最新文献

Purpose: Bacterial infections seriously affect the health of patients and their incidence is very high. Photothermal therapy has shown promising prospects in the treatment of bacterial infections as it can effectively kill bacteria and reduce inflammation. Black phosphorus (BP) is an emerging nanoparticle that can generate heat under the action of near-infrared light, it can safely and effectively kill bacteria through photothermal therapy. In this experiment, black phosphorus was used as a photothermal agent to kill bacteria and strontium ions were loaded onto BP to enhance its stability and antibacterial performance.

Methods: BP was obtained by liquid phase exfoliation and Sr²⁺ was loaded onto the surface of BP by electrostatic interaction.

Results: BP-Sr was synthesized via electrostatic interactions and characterized using various techniques. The cytocompatibility of BP-Sr was evaluated by CCK8 assay and live/dead staining which showed no significant cytotoxicity with a concentration not exceed 50 μg/mL. Meanwhile, the antibacterial effects showed 99% of bacteria died after 10 min under the action of a 2 W/cm² laser and the structure of bacteria was destroyed. Finally, the transcriptomic results suggest that bacteria death may be related to membrane destruction, metabolic disorders, and transport damage. HE staining and Gram staining also showed that inflammation was significantly alleviated after laser treatment.

Conclusion: These findings propose a great solution for bacterial infection and also enrich the theoretical framework supporting the application of BP-Sr in the field of antibiosis.

Background: Osteoarthritis (OA), a prevalent joint disease, causes immense suffering to thousands of patients, impairing their mobility and diminishing their quality of life. Current treatment methods primarily rely on analgesics or anti-inflammatory drugs to alleviate symptoms but fail to achieve the desired therapeutic outcome.

Methods: To better realize therapeutic effects of OA, procyanidins (PAs), as a type of plant flavonoids with strong antioxidant and anti-inflammatory activities, were designed to self-assembly with well-dispersible Pluronic F127 (PF127) through the hydrogen-bond interaction to present an injectable, biocompatibility PA nanospheres.

Results: These nanospheres significantly increased the cell viability in mouse L929 fibroblasts and ADTC5 chondrocytes compared with unassembled PAs. In addition, the self-assembling PAs/PF127 nanospheres enhanced the protein expression of collagen (COL1A1 and COL3A1) in fibroblasts, and the expression of glycosaminoglycan and COL2A1 was also higher than unassembled PAs in chondrocytes, this heralded the potential to achieve OA repair strategies at the cellular level. In an enzymolysis model of rat OA, PAs/PF127 nanospheres significantly reduce joint space swelling in the early stages of cartilage destruction and accelerate the formation of subchondral bone and cartilaginous surface.

Implication: This study offers valuable insights into the preparation of novel PA nanospheres for effective repair of OA.

Background: Diabetic foot ulcers (DFUs) are often associated with persistent inflammatory response, impaired macrophage polarization, and slow vascular regeneration. Existing treatments cannot be adapted to wounds and do not achieve the desired therapeutic effects. The high porosity of biomaterials induces more M2 macrophages, while the natural compound kaempferol inhibits the expression of matrix metalloproteinase 9 (MMP9) and thus inhibits the associated inflammatory and immunological responses.

Methods: portable electrospinning dressings (PEDs) were prepared from the spinning solution using a portable electrospinning device. The material properties of PEDs were examined by scanning electron microscope, contact angle tester and WVTR-C3. Then, the in vitro biocompatibility of the dressings was evaluated using NIH3T3 cells. The in vivo wound healing efficacy of the dressings was analyzed in the diabetic wound model rats. Histological and immunofluorescence staining were performed to determine the status of epithelization, collagen deposition, MMP9 expression, macrophage polarization, inflammation response and angiogenesis.

Results: Material science experiments have shown that the dressing has optimal fiber micromorphology and good water vapor transport properties (WVTR: 4.88 kg m^-2 24h^-1); in vivo, diabetic wound experiments have shown that the high porosity and pharmacological effects of PED4 can mutually promote the rapid healing of diabetic wounds (healed 95.9% on day 15), facilitate the transformation of macrophages from M1-type to M2-type and regulate the expression of MMP9.

Conclusion: Portable electrospinning dressings equipped with kaempferol not only better fit irregular wounds, but also promote wound healing through MMP9 and macrophage polarization. Thus, PEDs show great promise for advancing research of personalized diabetic wound healing.

Background: Osteoporosis is a major public health concern characterized by decreased bone density. Among various therapeutic strategies, apoptotic extracellular vesicles (ApoEVs) have emerged as promising agents in tissue regeneration. Specifically, T cell-derived ApoEVs have shown substantial potential in facilitating bone regeneration. However, it remains unclear whether ApoEVs can promote bone mass recovery through enzymatic activity mediated by membrane surface molecules. Therefore, this study aimed to investigate whether T cell-derived ApoEVs could promote bone mass recovery in osteoporosis mice and reveal the underlying mechanisms.

Methods: ApoEVs were isolated through sequential centrifugation, and their proteomic profiles were identified via mass spectrometry. Western blot and immunogold staining confirmed the enrichment of CD39 and CD73 on ApoEVs. The role of CD39 and CD73 in hydrolyzing adenosine triphosphate (ATP) to adenosine was evaluated by quantifying the levels of ATP and adenosine. Inhibitors of CD39 and CD73, and an A2BR antagonist were used to explore the molecular mechanism of ApoEVs in promoting bone regeneration.

Results: ApoEVs significantly reduced bone loss and promote the osteogenic differentiation of BMMSCs in ovariectomy (OVX) mice. We observed increased levels of extracellular ATP and a decrease in CD39 and CD73, key enzymes in ATP-to-adenosine conversion in bone marrow of OVX mice. We found that ApoEVs are enriched with CD39 and CD73 on their membranes, which enable the hydrolysis of extracellular ATP to adenosine both in vitro and in vivo. The adenosine generated by ApoEVs inhibits the inflammatory response and promotes osteogenesis through A2BR and downstream PKA signaling.

Conclusion: T cell-derived ApoEVs are enriched with CD39 and CD73, enabling them to hydrolyze extracellular ATP to adenosine, thereby promoting bone regeneration via A2BR and PKA signaling pathway. Our data underscore the substantive role of T cell-derived ApoEVs to treat osteoporosis, thus providing new ideas for the development of ApoEVs-based therapies in tissue regeneration.

Introduction: Owing to its high prevalence, colossal potential of chemoresistance, metastasis, and relapse, breast cancer (BC) is the second leading cause of cancer-related fatalities in women. Several treatments (eg, chemotherapy, surgery, radiations, hormonal therapy, etc.) are conventionally prescribed for the treatment of BC; however, these are associated with serious systemic aftermaths. In this research, we aimed to design a multiprong targeting strategy for concurrent action against different phenotypes of BC (MCF-7 and SK-BR-3) and tumor-associated macrophages (TAMs) for relapse-free treatment of BC.

Methods: Paclitaxel (PTX) and tamoxifen (TMX) co-loaded chitosan (CS) nanoparticles (NPs) were prepared using the ionic-gelation method and optimized using the Design Expert^® software by controlling different material attributes. For selective targeting through CD44-receptors that are heavily expressed on the BC cells and TAMs, the fabricated NPs (PTX-TMX-CS-NPs) were functionalized with hyaluronic acid (HA) as a targeting ligand.

Results: The optimized HA-PTX-TMX-CS-NPs exhibited desired physicochemical properties (PS ~230 nm, PDI 0.30, zeta potential ~21.5 mV), smooth spherical morphology, high encapsulation efficiency (PTX ~72% and TMX ~97%), good colloidal stability, and biphasic release kinetics. Moreover, the lowest cell viability depicted in MCF-7 (~25%), SK-BR-3 (~20%), and RAW 264.7 cells (~20%), induction of apoptosis, cell cycle arrest, enhanced cell internalization, and alleviation of MCF-7 and SK-BR-3 migration proved the superior anticancer potential of HA-PTX-TMX-CS-NPs compared to unfunctionalized NPs and other control medicines.

Conclusion: HA-functionalization of NPs is a promising multiprong strategy for CD44-receptors-mediated targeting of BC cells and TAMs to mitigate the progression, metastasis, and relapse in the BC.

Purpose: To improve the oral absorption of relugolix (RLGL), which has low oral bioavailability due to its low solubility and being a substrate of P-glycoprotein (P-gp). A solid self-microemulsifying drug delivery system of relugolix (RLGL-S-SMEDDS) was prepared and evaluated in vitro and in vivo.

Methods: The composition of the solid self-microemulsifying drug delivery system (S-SMEDDS) was selected by solubility study and pseudo-ternary phase diagram, and further optimized by Design-Expert optimization design. The optimized RLGL-S-SMEDDS were evaluated in terms of particle size, zeta potential, morphology analysis, thermodynamic stability, drug release, flow properties, transporter pathways in Caco-2 cells, the influence of excipients on the intestinal transporters, transport within Caco-2 cell monolayers and transport in lymphocyte. In vivo pharmacokinetic study and toxicological study were also conducted.

Results: The optimum formulation for self-microemulsifying drug delivery system (SMEDDS) consists of Ethyl Oleate (26% of the weight), Solutol HS15 (49% of the weight), Transcutol HP (25% of the weight) and loaded relugolix (4.8 mg/g). The S-SMEDDS was then formed by adsorbing 2.4 g of SMEDDS onto 1 g of hydrophilic-200 silica. In phosphate buffered saline (PBS) (pH 6.8) release medium containing 1% tween 80, the vitro release studies showed 86% cumulative drug release for RLGL-S-SMEDDS and 3.6% cumulative drug release for RLGL suspensions. In vitro cellular uptake experiments revealed that the uptake of RLGL-S-SMEDDS by Caco-2 cells was three times higher than that of free RLGL, and that S-SMEDDS can enhance the drug absorption through lymphatic absorption and inhibition of intestinal transporter. In vivo pharmacokinetic evaluation demonstrated that the oral bioavailability of RLGL-S-SMEDDS was 1.9 times higher than that of RLGL-suspensions. There was no apparent cardiac, hepatic, splenic, pulmonary or renal toxicity on the surface discovered by pathological analysis after oral administration.

Conclusion: It is evident that S-SMEDDS may be a safe and effective method to improve oral absorption of drugs with low oral bioavailability.

Background: Colorectal cancer (CRC) is a highly malignant and aggressive gastrointestinal tumor. Due to its weak immunogenicity and limited immune, cell infiltration lead to ineffective clinical outcomes. Therefore, to improve the current prophylaxis and treatment scheme, offering a favorable strategy efficient against CRC is urgently needed.

Methods: Here, we developed a nanovaccine (LBP-CD155L NVs) loaded with CD155 gene in liposome, which was modified by Lycium barbarum polysaccharides (LBP) through electrostatic interaction. The nanovaccine was characterized by transmission electron microscopy and Zetasizer. It was evaluated in vitro, where NVs facilitated the endocytosis and maturation of DCs, and in vivo, where NVs improved the efficacy of prophylaxis and therapy. In addition, further confirmed the mechanisms by how TLR4 and MGL synergistic pathway endow the nanovaccines towards dendritic cells (DCs). Finally, the safety and tumor immunosuppressive microenvironment were evaluated in the CRC tumor-bearing mouse model.

Results: We successfully developed a nanovaccine that facilitates the endocytosis and maturation of DCs via a synergistic pathway involving TLR4 and MGL, which endow the nanovaccines towards dendritic cells (DCs) and promote the differentiation, thereby enhancing the cytotoxicity of CD8⁺T cells. Consequently, LBP-CD155L NVs can potentiate the efficacy of prophylactic and therapeutic administration in a mouse CRC model, as evidenced by decreased infiltration of myeloid-derived suppressor cells (MDSCs) and Tregs, reprogrammed the macrophage phenotypes, which promoted polarization from M2-like macrophages to M1-like macrophages, increased infiltration of effector T cells. Prophylactic and therapeutic combination regimens with anti-PD-1 treatment demonstrate synergism that stimulates T-cell infiltration into tumors and counteracts immunosuppression, leading to remarkable tumor remission and enhancing the efficacy of immune checkpoint therapy in solid tumors.

Conclusion: Our work provided that LBP-CD155L NVs may serve as a promising tool for reversing tumor immunosuppressive microenvironment and enhancing ICB therapy in CRC.

Purpose: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. Oxaliplatin (OXA) is currently the primary chemotherapeutic agent for CRC, but its efficacy is limited by the tumor microenvironment (TME). Here, we present a combined approach of chemotherapy and TME modulation for CRC treatment. A multifunctional nanosystem (Rg3-Lip-OXA/CaO₂) was established using Ginsenoside Rg3 liposomes targeting glucose transporter 1 overexpressed on the surface of CRC cells to co-deliver OXA and calcium peroxide (CaO₂).

Methods: The CaO₂ nanoparticles were synthesized via the CaCl₂-H₂O₂ reaction under alkaline conditions and characterized using X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). Rg3-Lip-OXA/CaO₂ was prepared through a thin-film hydration approach and characterized; additionally, its stability and release behavior were studied. The O₂, H₂O₂, and Ca²⁺ generation ability of Rg3-Lip-OXA/CaO₂ in solution and HCT116 cells were measured. The in vitro cellular uptake was observed via fluorescence microscope and flow cytometry. In vitro cytotoxicity was evaluated using the CCK-8 assay, flow cytometry, and live/dead cell staining. The in vivo targeting effect as well as antitumor efficacy were determined in HCT116 tumor-bearing mice. Finally, the acute toxicity of Rg3-Lip-OXA/CaO₂ was investigated in ICR mice to explore its safety.

Results: The XRD and XPS analyses confirmed the successful synthesis of CaO₂ nanoparticles. The Rg3-Lip-OXA/CaO₂ exhibited an average particle size of approximately 92.98 nm with good stability and sustained release behavior. In vitro and in vivo studies confirmed optimal targeting by Rg3-Lip and demonstrated that the nanosystem effectively produced O₂, H₂O₂ and Ca²⁺, resulting in significant cytotoxicity. Additionally, in vivo studies revealed substantial tumor growth suppression and reduced tumor-associated fibroblasts (TAFs) and collagen. Acute toxicity studies indicated that Rg3-Lip-OXA/CaO₂ markedly reduced the toxicity of chemotherapeutic drugs.

Conclusion: This multifunctional nanosystem enhances chemotherapy efficacy and reduces toxicity, offering a promising approach for optimizing CRC treatment and potential clinical application.

Purpose: The main purpose of the study was the formulation development of nanogels (NHs) composed of chondroitin sulfate (CS) and low molecular weight chitosan (lCH), loaded with a naringenin-β-cyclodextrin complex (NAR/β-CD), as a potential treatment for early-stage diabetic retinopathy.

Methods: Different formulations of NHs were prepared by varying polymer concentration, lCH ratio, and pH and, then, characterized for particle size, zeta potential, particle concentration (particles/mL) and morphology. Cytotoxicity and internalization were assessed in vitro using Human Umbilical Vein Endothelial Cells (HUVEC). The NAR/β-CD complex was prepared and evaluated for morphology, complexation efficiency, and solubility. Finally, the most promising NH prototype was loaded with NAR/β-CD (NH@NAR/β-CD) and further characterized for encapsulation efficiency, loading capacity, opacity and cytotoxicity on HUVEC; in vitro release test and DPPH assay were performed to investigate NH capability to sustain NAR release and NH@NAR/β-CD antioxidant properties, respectively.

Results: NH properties were influenced by polymer concentration, lCH ratio, and pH. N3 (0.5 mg/mL; lCH=1.5:1; pH = 5) and N9 (0.5 mg/mL; lCH=1:1; pH = 5) showed optimal characteristics, including small size (<350 nm) and positive zeta potential, facilitating cellular uptake. The NAR/β-CD complex showed 71% complexation efficiency and enhanced NAR solubility. Since characterized by superior properties and better in vitro biocompatibility, N3 was loaded with NAR/β-CD. N3@NAR/β-CD capability to sustain in vitro NAR release, radical scavenging activity and in vitro biocompatibility were finally demonstrated.

Conclusion: The physico-chemical properties of N3@NAR/β-CD were responsible for their cell uptake, suggesting their potential to target retinal endothelial cells. The high NAR/β-CD complexation efficiency and the sustained NAR release over 72 hours could guarantee the maintenance of an effective drug concentration at the damage site while reducing the injection number. Further studies about the safety and the effectiveness of the intravitreal injection of NHs@NAR/β-CD will be performed on a diabetic animal model.