查看更多>>摘要：? 2022 Acta Materialia Inc.Excessive secretion of cytokines (such as APRIL and BAFF) in the bone marrow microenvironment (BMM) plays an essential role in the formation of relapsed or refractory multiple myeloma (MM). Blocking the binding of excessive cytokines to their receptors is becoming a promising approach for MM therapy. Here, we proposed a strategy of engineering cell membrane-based nanovesicles (NVs) to reconstruct B cell maturation antigen (BCMA), a receptor of APRIL and BAFF, to capture excess APRIL/BAFF in BMM as a bait protein. Our results showed that reconstructed BCMA expressed on the membrane of NVs (Re-BCMA-NVs) retained the ability of binding to soluble and surface-bound APRIL/BAFF in BMM. Consequently, Re-BCMA-NVs blocked the activation of the NF-κB pathway, downregulating the expression of anti-apoptosis genes and cell cycle-related genes, and hence inhibiting MM cell survival. Importantly, Re-BCMA-NVs showed a synergistic anti-MM effect when administrated together with bortezomib (BTZ) in vitro and in vivo. Our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to BTZ-based therapy. Statement of significance: Excessive APRIL and BAFF is reported to promote the survival of MM cell and facilitate the formation of resistance to bortezomib therapy. In this study, we bioengineered cell membrane derived reconstructed BCMA nanovesicles (Re-BCMA-NVs) to capture both soluble and cell-surface APRIL and BAFF. These NVs inhibited the activation of NF-κB pathway and thus inhibit the survival of MM cells in 2D, 3D and subcutaneous mouse tumor models. Importantly, Re-BCMA-NVs showed a synergistic anti-MM effect when administrated together with bortezomib in vitro and in vivo. Taken together, our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to bortezomib-based therapy.
查看更多>>摘要：? 2022Helicobacter pylori is a causative factor of various gastrointestinal tract diseases. As clinical antibiotic-based therapy for H. pylori infection might induce bacterial drug resistance, the in vivo eradication of H. pylori remains a huge challenge. In the present study, monoclonal antibody-conjugated liposomes loaded with indocyanine green (ICG) (HpAb-LiP-ICG) were successfully developed for targeted photoacoustic (PA) imaging-guided sonodynamic therapy (SDT) of H. pylori infection in vivo. HpAb-LiP-ICG showed high stability and favorable biocompatibility in acidic environment (pH 1.5) and was used for treating H. pylori-infected mice through oral administration. PA imaging showed that HpAb-LiP-ICG could precisely recognize and target H. pylori in the stomach. Following the targeting of HpAb-LiP-ICG to H. pylori, ICG was activated to generate singlet oxygen (1O2) for eliminating H. pylori under ultrasound (US) irradiation. Pathological analysis revealed that the HpAb-LiP-ICG-mediated SDT eradicated H. pylori without unintended toxicity to normal tissues. In conclusion, the HpAb-LiP-ICG-mediated SDT might shed new light on treating H. pylori infection, indicating the clinical translational prospects of this therapy in near future. Statement of significance: Traditional antibiotic-based therapy for Helicobacter pylori infections suffers from the risk of drug resistance. To meet this challenge, a monoclonal antibody-conjugated nanoliposome loaded with indocyanine green (ICG) (HpAb-LiP-ICG) was successfully developed, and efficient eradication of H. pylori was achieved in vivo by visual sonodynamic therapy (SDT). HpAb-LiP-ICG exhibited biocompatibility, targeting, and stability in the acidic microenvironment. Under ultrasound (US) irradiation in vitro, the HpAb-LiP-ICG nanoliposomes accumulated on the surface of H. pylori were activated to produce adequate singlet oxygen (1O2) to eliminate H. pylori. Gastric mucous tissues infected with H. pylori recovered to the normal state after HpAb-LiP-ICG-mediated SDT without side effects, thus highlighting the clinical translational prospects of the prepared HpAb-LiP-ICG nanoliposome in near future.
查看更多>>摘要：? 2022 Elsevier LtdRecently, nitric oxide (NO) has received increasing interest in combat against bacteria-induced infections because of its ability to sensitize and enhance the antibacterial effectiveness of many therapeutic approaches such as antibiotics. However, high-efficient loading and controlled release of NO remain a big challenge. In the present work, a type of gold nanostar/hollow polydopamine Janus nanostructure (GNS/HPDA JNPs) with precise near infrared (NIR)-controlled NO release property was fabricated using a facile seed-mediated method. Upon NIR laser irradiation, the NO-releasing GNS/HPDA JNPs (GNS/HPDA-BNN6) exhibited a synergistic photothermal and NO antibacterial effect by significantly inhibiting the growth and biofilm formation of both Gram-negative and Gram-positive bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA). An in-depth mechanism study revealed that two pathways were mainly involved in the synergistic photothermal and NO antibacterial effect. In one pathway, the synergistic effect severely destroyed the bacterial membrane by causing leakage of intracellular components such as DNA. In another pathway, the synergistic effect largely disturbed bacterial metabolism by regulating relative metabolic genes, followed by enhancing ROS generation to cause intracellular GSH depletion and DNA damage. More importantly, the synergistic effect significantly diminished the drug resistance of MRSA by downregulating the expression of the drug-resistant gene mecA and some relative multidrug efflux pumps (e.g., SepA and Tet38). An in vivo evaluation using a rat model with MRSA-infected wounds indicated that the synergistic photothermal and NO effect of GNS/HPDA-BNN6 can effectively eliminate MRSA from wounds, thereby alleviating inflammation and promoting wound healing. Statement of significance: Multidrug-resistant (MDR) bacteria have become a big threat to mankind, and therefore, the development of innovative antibacterial agents with high antibacterial efficiency is urgently required. Nanomaterial-mediated nitric oxide (NO) therapy is a promising strategy to effectively combat MDR bacteria through a synergistic antibacterial effect. Here, a gold nanostar/hollow polydopamine Janus nanostructure with precise near infrared (NIR) light-controlled NO release property (GNS/HPDA-BNN6) was developed. Both in vitro and in vivo evaluations demonstrated that GNS/HPDA-BNN6 could effectively eliminate methicillin-resistant Staphylococcus aureus (MRSA) from infected wounds and promote wound healing through a synergistic photothermal and NO therapeutic effect. Remarkably, the synergistic effect significantly diminished the drug resistance of MRSA by downregulating the expression of some drug-resistant genes and multidrug efflux pumps.
查看更多>>摘要：? 2022 Acta Materialia Inc.The development of intelligent designs of new antibacterial modalities for diagnosing and treating chronic multidrug-resistant bacterial infections is an urgent need, but achieving the precisive theranostic in response to specific inflammatory microenvironments remains a great challenge. This paper describes our work designing and demonstrating infection microenvironment-activated core-shell Gd-doped Bi2S3@Cu(II) boron imidazolate framework (Bi2S3:Gd@Cu-BIF) nanoassemblies. Upon exposure to a single beam of 808 nm laser, Bi2S3:Gd@Cu-BIF nanoassemblies showed exceptional photothermal conversion (η = 52.6%) and produced several cytotoxic reactive oxygen species, such as singlet oxygen and hydroxyl radicals, by depleting the intracellular glutathione and in-situ catalyzing the decomposition of endogenous hydrogen peroxide in the inflammatory microenvironment. The broad-spectrum antibacterial properties of nanoassemblies were confirmed to be effective against Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) with an inhibition rate of 99.99% in vitro. Additionally, in vivo wound-healing studies revealed that Bi2S3:Gd@Cu-BIF nanoassemblies could serve as an effective wound spray to accelerate healing following MRSA infections via photothermal/chemodynamic (PTT/CDT) synergistic therapy. The effective wound healing rate in the synergistic treatment group was 99.8%, which is higher than the 69.5% wound healing rate in the control group. Furthermore, magnetic resonance and computed tomography dual-modal imaging mediated by Bi2S3:Gd@Cu-BIF nanoassemblies also exhibits promising potential as an integrated diagnostic nanoplatform. Overall, this work provides useful insights for developing all-in-one theranostic nanoplatforms for clinical treatment of drug-resistant bacterial infections. Statement of significance: New treatments and effective diagnostic strategies are critical for fighting drug-resistant bacterial infections. Infection microenvironment-activated Bi2S3@Cu-BIF nanoassemblies can simultaneously increase eigen temperature and generate cytotoxic reactive oxygen species, such as singlet oxygen and hydroxyl radicals, under near-infrared laser irradiation, achieving the synergistic effect of photothermal and chemodynamic therapy, which has been proven to be highly effective for inhibiting bacterial activity and speeding wound healing from methicillin-resistant Staphylococcus aureus infection. More importantly, the nanoassemblies could enable early precise visualized detection of bacterial abscess using magnetic resonance/computed tomography dual-modal bio-imaging techniques.
查看更多>>摘要：? 2022Camptothecin (CPT) is a potent anticancer agent for the treatment of colorectal cancer; however, it exhibits some limitations, including poor solubility, low stability, and low bioavailability via oral administration, which restrict its usability in clinical treatments. In addition, overproduction of reactive oxygen species (ROS) during chemotherapy induces drug resistance and severe intestinal side effects. In this study, silica-installed ROS scavenging nanoparticles (siRNP) with 50–60 nm in diameter were employed to overcome the aforementioned drawbacks of CPT. The solubility of CPT was significantly improved by incorporating it into the core of the nanoparticle, forming CPT-loaded siRNP (CPT@siRNP). The anticancer activity of CPT@siRNP against colorectal cancer cells (C-26) in vitro was significantly improved as compared to free CPT through higher efficiency of intracellular internalization and induction of apoptosis. Owing to its antioxidant properties, CPT@siRNP reduced cytotoxicity to normal endothelial cells, which was in sharp contrast to the high toxicity of free CPT. Oral administration of CPT and CPT@siRNP to the C-26 tumor-bearing mice exhibited antitumor activity, accompanied by effective suppression of tumor growth. Although CPT treatment suppressed tumor progression, it caused severe side effects, including intestinal damage and significant bodyweight loss. Interestingly, such noticeable side effects were not observed in the mice treated with CPT@siRNP, and the effect of tumor growth inhibition tended to be similar to or higher than that of CPT treatment. The results obtained in this study indicate that CPT@siRNP is a potential therapeutic nanomedicine for the treatment of colon cancer. Statement of significance: Here we employed silica-containing antioxidant nanoparticle (siRNP) as promising oral delivery nanocarrier of campothecin (CPT) to treat colon cancer. The design of siRNP via covalent conjugation of antioxidant nitroxide radicals and the silanol groups in the polymer backbone contributes to a significant increase in the absorption of hydrophobic drug molecules inside the core and enhances the stability of nanoparticles in the gastrointestinal environment for oral drug delivery. CPT-loaded siRNP (CPT@siRNP) significantly improved solubility of CPT. As compared to free CTP, the CPT@siRNP treatment showed a significantly higher toxicity to colon cancer cell, inhibition of cancer cell migration, and induction of apopotosis. With the antioxidant feature, siRNP also significantly suppressed the intestinal side effects caused by CPT treatment in tumor-bearing mouse model.
查看更多>>摘要：? 2022 Acta Materialia Inc.Chronic bacterial prostatitis (CBP) occurs frequently in the male population and significantly influences quality of life. Antibiotics are the main strategy for managing chronic bacterial prostatitis; however, most antibiotics have low efficacy due to their poor penetration of prostate tissues. To overcome this challenge, we fabricated cefpodoxime proxetil (CPD)-loaded reactive oxygen species (ROS)-responsive nanoparticles (NPs) for targeted treatment of CBP. These NPs were modified with folic acid (FA) and could be effectively internalized by bacteria-infected macrophages and prostatic epithelial cells because of the high expression of folate receptors (FRs) in these cells. In vitro cellular assays demonstrated that the CPD-loaded nanomedicine can obviously reduce proinflammatory cytokine expression in cells since the nanomedicine can efficiently eradicate cellular bacteria. In vivo imaging results verified that FA-modified nanomedicines can penetrate the prostatic epithelium and accumulate in the glandular lumen because FRs overexpression was also observed in the prostate tissues of CBP mice. Animal experiments demonstrated that FA-modified nanomedicine can remarkably relieve pelvic pain in CBP mice and dramatically decrease proinflammatory cytokine expression in prostate tissues via eradication of bacteria and scavenging of ROS. Our results provide a new strategy to deliver antibiotics for targeted therapy of CBP. Statement of significance: To overcome poor penetration of antibiotics in prostatic tissues, we developed an antibiotics-loaded ROS-responsive NPs for targeted treatment of CBP. We demonstrated that both bacteria-infected macrophages and prostatic epithelial cells have FRs overexpression, thus FA-modified NPs can be efficiently internalized by these cells. FA-modified NPs can penetrate the prostatic epithelium and accumulate in the glandular lumen via FRs-mediated endocytosis, and the accumulated NPs can smartly release their payload under high ROS microenvironment. A distinguished therapy outcome was obtained in murine CBP model since CPD-loaded NPs can efficiently eradicate the resident bacteria in prostate tissues and downregulate proinflammatory cytokine expression. Our work provides a practicable strategy to expand the application of antibiotics for management of CBP.
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