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1.
    
The cardiac fibrosis caused by excessive deposition of collagen and the fibro-inflammatory cascade reaction severely impedes the cardiac regenerative efficiency after myocardial infarction (MI) so that the onefold treating target is far from satisfying therapeutic efficacy. Herein, a yes-associated protein (YAP)-suppressive nanodrug-crosslinked self-immunoregulatory polysaccharide injectable hydrogel is fabricated for the first time. To this end, cationic liposomes loading YAP inhibitor verteporfin (Lipo-VP) is prepared and coated with oxidized fucoidan (OFu), a unique anti-inflammation polysaccharide, to form anti-fibrotic and immunoregulatory nanodrug (OFu-Lipo-VP). The coated fucoidan itself acts as a reactive oxygen species (ROS) scavenger and inflammation regulator, thus facilitating angiogenesis function by eliciting endogenous vascular endothelial growth factor secretion of macrophages. Then an injectable hydrogel (termed as OFu-Lipo-VP-PGA) is formed through addition reaction between the aldehyde groups of OFu-Lipo-VP and the thiol groups of thiol-modified poly(γ-glutamic acid) (PGA-SH), where the thiol groups can also aid in eliminating ROS. The acute MI models are established and the infarcted male rats are treated with this injectable OFu-Lipo-VP-PGA hydrogel after MI. The outcomes at 28 days post-surgery indicate efficient restoration of cardiac functions and attenuation of cardiac fibrosis. This study opens up a new possibility for MI treatment with immunoregulatory and antifibrotic injectable polysaccharide-based hydrogel.  相似文献   

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A conductive engineered cardiac patch (ECP) can reconstruct the biomimetic regenerative microenvironment of an infarcted myocardium. Direct ink writing (DIW) and 3D printing can produce an ECP with precisely controlled microarchitectures. However, developing a printed ECP with high conductivity and flexibility for gapless attachment to conform to epicardial geometry remains a challenge. Herein, an asymmetrical DIW hydrophobic/hydrophilic membrane using heat-processed graphene oxide (GO) ink is developed. The “Masked spin coating” method is also developed that leads to a microscale GO (hydrophilic)/reduced GO (rGO, hydrophobic) physiological sensor, as well as a macroscale moisture-driven GO/rGO actuator. Depositing mussel-inspired polydopamine (PDA) coating on the one side of the DIW rGO , the ultrathin (approximately 500 nm) PDA-rGO (hydrophilic)/rGO (hydrophobic) microlattice (DrGOM) ECP is bestowed with the flexibility and moisture-responsive actuation that allows gapless attachment to the curved surface of the epicardium. Conformable DrGOM exhibits a promising therapeutic effect on rats' infarcted hearts through conductive microenvironment reconstruction and improved neovascularization.  相似文献   

3.
    
Tumor precision therapy and preventing tumor recurrence and metastasis are the main challenges to tumor eradication. Herein, an apoptotic body-based vehicle with imaging navigation is developed for precise tumor delivery and photothermal-immunotherapy by IR820-conjugated apoptotic body loaded with R848 nanoparticles. The apoptotic body serves as ammunition stores as well as vehicle drive engines, while IR820 acts as a fluorescence imaging navigation and photothermal controlling system. The apoptotic body vehicle can deliver the ammunition to tumor and achieve deep penetration by macrophage-hitchhiking. Fluorescence imaging navigation opens a control window for photothermal treatment, followed by photothermal triggering of in situ vaccine formation. Further, CD47 antibody loaded hydrogel strengthens innate and adaptive immunity, simultaneously the polarization of macrophages regulates the immunosuppressive microenvironment to further promote the combined antitumor immunotherapy. With breast tumor (4T1)-bearing mice model, the apoptotic body vehicle performs excellent therapeutic efficacy for primary tumor, distant tumor, tumor metastasis, and recurrence prevention.  相似文献   

4.
    
Hydrogel-based engineered cardiac patches (ECP) hold great promise as potential treatment options for myocardial infarction (MI). However, optimizing the preparation of ECP with better biocompatibility, mechanical stability, and adaptation to MI repair remains a challenge. In this study, a chitosan (CS) hydrogel with good mechanical robustness through programmed control of hydrogen bonding is constructed to adapt to the continuous beating of myocardial tissue. With the synergistic effects of lipoic acid (TA), proanthocyanidins (PAs), and Eu3+, a functional platform capable of improving mitochondrial function, antioxidation, and pro-vascularization is further constructed for the adaptive repair of the MI microenvironment. The fabricated functionalized chitosan hydrogel (CS/TA@PAs-Eu) possessed good mechanical stability and ionic conductivity, showing the potential for long-term adaptation to myocardial tissue pulsation. Also, the CS/TA@PAs-Eu hydrogel promoted cardiomyocytes (CMs) maturation and functionalization, and effectively improved mitochondrial function, scavenged reactive oxygen species (ROS) as well as promoted angiogenesis. Animal studies indicated that the CS/TA@PAs-Eu hydrogel can perform adaptive repair of MI to prevent left ventricular (LV) remodeling and restore cardiac function. This study highlights a functionalized hydrogel ECP with good biocompatibility and mechanical robustness for the adaptive repair of MI.  相似文献   

5.
    
Currently, although conducting polymers have exhibited potential electrophysiological modulation, designing bioinspired ultra-histocompatible conducting polymers remains a long-standing challenge. Moreover, the water dispersibility, conductivity, and biocompatibility of conducting polymers are incompatible, which restricts their application in tissue engineering. Herein, a multilevel template dispersion strategy is presented to produce poly(3,4-ethylenedioxythiophene):(dextran sulfate/carboxymethyl chitosan) (PEDOT:(DSS/CMCS)) with biocompatibility superior to that of commercial poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) without sacrificing processability and conductivity. The PEDOT:(DSS/CMCS) and oxidized dextran solutions form an injectable PEDOT-based hydrogel (PDCOH) mediated by dynamic covalent imine bonds under mild conditions. The PDCOH has a tissue-matched modulus and conductivity to adapt to the mechanical environment of dynamic tissue and modulate fibrosis-induced electrical decoupling. The PDCOH combined with adipose-derived stem cells demonstrates superior cardiac repair effects over cell suspensions and nonconductive hydrogels, inhibiting ventricular remodeling, reducing fibrous scarring, promoting vascular regeneration, and restoring electrophysiological and pulsatile functions.  相似文献   

6.
    
Photoresponsive drug delivery systems (PDDSs) have emerged as a promising toolbox for drug delivery, offering precise control over the site, duration, and dosage of light-triggered medication. It allows controlled drug release, photo-triggered targeting, diagnosis, and treatment, improving the precision and efficacy of therapies for various diseases. Despite progress in designing different PDDSs, clinical translation has been limited due to various obstacles. Herein, this review article focuses on three critical challenges of PDDSs: 1) accumulation at diseased lesions, 2) precision of light irradiation, and 3) penetration of light in tissues. Also, this article summarizes and discusses current advancements and strategies to address these challenges. Overall, it emphasizes the need to clarify the current challenges from bench to bedside and develop strategies to enhance therapeutic outcomes, increase compatibility and patient compliance, and unlock the possibilities in different clinical therapies.  相似文献   

7.
    
Protein therapy offers promising prospects for the treatment of various important diseases, thus it is highly desirable to develop a robust carrier that can deliver active proteins into cells. The development of a novel protein delivery platform based on the self‐assembly of multiarmed amphiphilic cyclodextrins (CDEH) is reported. CDEH can self‐assemble into nanoparticles in aqueous solution and achieve superior encapsulation of protein (loading capacity > 30% w/w) simply by mixing with protein solution without introducing any subsequent cumbersome steps that may inactivate proteins. More importantly, CDEH nanovehicles can be easily further modified with various targeting groups based on host–guest complexation. Using saporin as a therapeutic protein, AS1411‐aptamer‐modified CDEH nanovehicles can preferentially accumulate in tumors and efficiently inhibit tumor growth in a MDA‐MB‐231 xenograft mouse model. Moreover, folate‐targeted CDEH nanovehicles can also deliver Cas9 protein and Plk1‐targeting sgRNA into Hela cells, leading to 47.1% gene deletion and 64.1% Plk1 protein reduction in HeLa tumor tissue, thereby effectively suppressing the tumor progression. All these results indicate the potential of targeted CDEH nanovehicles in intracellular protein delivery for improving protein therapeutics.  相似文献   

8.
    
Intracellular protein delivery presents a novel promising prospect for cell biology research and cancer therapy. However, inefficient cellular uptake and lysosomal sequestration hinder productive protein delivery into the cytosol. Here, a library of 16 preselected sequence‐defined oligoaminoamide oligomers is evaluated for intracellular protein delivery. All oligomers, containing polyethylene glycol (PEG) for shielding and optionally folic acid as targeting ligand, manifest cellular internalization of disulfide‐conjugated enhanced green fluorescent protein (EGFP). However, only a PEGylated folate‐receptor targeted two‐arm oligomer (729) containing both arms terminally modified with two oleic acids shows persistent intracellular protein survival and nuclear import of nlsEGFP (which contains a nuclear localization sequence) in folate‐receptor‐positive KB carcinoma cells, validating both effective endolysosomal escape and following subcellular transport. Furthermore, using ribonuclease A as a therapeutic cargo protein, among the tested oligomers, the oleic acid modified targeted two‐arm oligomers exert the most significant tumor cell killing of KB tumor cells. An investigation of structure–activity relationship elucidates that the incorporated oleic acids play a vital role in the enhanced intracellular protein delivery, by promoting stable formation of 25–35 nm lipo‐oligomer protein nanoparticles and by membrane‐active characteristics facilitating intracellular cytosolic delivery.  相似文献   

9.
    
Efficient oral administration of protein‐based therapeutics faces significant challenges due to degradation from the highly acidic conditions present in the stomach and proteases present in the digestive tract. Herein, investigations into spike‐covered sunflower sporopollenin exine capsules (SECs) for oral protein delivery using bovine serum albumin (BSA) as a model drug are reported and provide significant insights into the optimization of SEC extraction, SEC loading, and controlled release. The phosphoric‐acid‐based SEC extraction process is optimized. Compound loading is shown to be driven by the evacuation of air bubbles from SEC cavities through the porous SEC shell wall, and vacuum loading is shown to be the optimal loading method. Three initial BSA‐loading proportions are evaluated, leading to a practical loading efficiency of 22.3 ± 1.5 wt% and the determination that the theoretical maximum loading is 46.4 ± 2.5 wt%. Finally, an oral delivery formulation for targeted intestinal delivery is developed by tableting BSA‐loaded SECs and enteric coating. BSA release is inhibited for 2 h in simulated gastric conditions followed by 100% release within 8 h in simulated intestinal conditions. Collectively, these results indicate that sunflower SECs provide a versatile platform for the oral delivery of therapeutics.  相似文献   

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11.
    
Photodynamic therapy (PDT) is a well‐established clinical treatment modality for various diseases. However, reactive oxygen species (ROS) generated by photosensitizers(PS) under proper irradiation exhibits the extremely short life span (<200 ns) and severely limited diffusion distance (20 nm), so the damage of ROS to biomolecules, especially DNA, is strongly confined to the immediate vicinity of ROS generation. In this report, an efficient nuclear‐targeted delivery strategy is proposed by using TAT and RGD peptides co‐conjugated mesoporous silica nanoparticles (MSNs) as PS carriers. The conjugation of TAT peptides enable the nuclear penetration of MSNs for efficient accumulation of PS inside nuclei. The intranuclear‐accumulated PS can generate ROS upon irradiation right inside nuclei to destroy DNA instantaneously. For the purpose of in vivo applications, the co‐conjugated RGD peptides endow the nuclear‐targeted delivery system with specific binding and recognition to tumor vasculature and tumor cell membranes for significantly enhanced specificity and reduced side effects. Through intravenous injection of these nanosystems in tumor‐bearing mice at a rather low PS dose of 2 mg/kg, tumor growth is efficiently inhibited by an extremely low irradiation dose of 6 J/cm2. This work presents a new paradigm for specific PDT with high efficacy and low side effects in vivo.  相似文献   

12.
    
Selective targeting of tumor cells and release of drug molecules inside the tumor microenvironment can reduce the adverse side effects of traditional chemotherapeutics because of the lower dosages required. This can be achieved by using stimuli‐responsive targeted drug delivery systems. In the present work, a robust and simple one‐pot route is developed to synthesize polymer‐gatekeeper mesoporous silica nanoparticles by noncovalent capping of the pores of drug‐loaded nanocontainers with disulfide cross‐linkable polymers. The method offers very high loading efficiency because chemical modification of the mesoporous nanoparticles is not required; thus, the large empty pore volume of pristine mesoporous silica nanoparticles is entirely available to encapsulate drug molecules. Furthermore, the polymer shell can be easily decorated with a targeting ligand for selective delivery to specific cancer cells by subsequent addition of the thiol‐containing ligand molecule. The drug molecules loaded in the nanocontainers can be released by the degradation of the polymer shell in the intracellular reducing microenvironment, which consequentially induces cell death.  相似文献   

13.
    
The principle cause of cardiovascular disease (CVD) is atherosclerosis, a chronic inflammatory condition characterized by immunologically complex fatty lesions within the intima of arterial vessel walls. Dendritic cells (DCs) are key regulators of atherosclerotic inflammation, with mature DCs generating pro‐inflammatory signals within vascular lesions and tolerogenic DCs eliciting atheroprotective cytokine profiles and regulatory T‐cell (Treg) activation. Here, the surface chemistry and morphology of synthetic nanocarriers composed of poly(ethylene glycol)‐b‐poly(propylene sulfide) copolymers to enhance the targeted modulation of DCs by transporting the anti‐inflammatory agent 1,25‐dihydroxyvitamin D3‐(aVD) and ApoB‐100‐derived antigenic peptide P210 are engineered. Polymersomes decorated with an optimized surface display and density for a lipid construct of the P‐D2 peptide, which binds CD11c on the DC surface, significantly enhance the cytosolic delivery and resulting immunomodulatory capacity of aVD in vitro. Weekly low‐dose intravenous administration of DC‐targeted, aVD‐loaded polymersomes significantly inhibit atherosclerotic lesion development in high‐fat‐diet‐fed ApoE?/? mice. The results validate the key role of DC immunomodulation during aVD‐dependent inhibition of atherosclerosis and demonstrate the therapeutic enhancement and dosage lowering capability of cell‐targeted nanotherapy in the treatment of CVD.  相似文献   

14.
    
Antibiotics have been established to induce indiscriminate detrimental effects on the gut commensal bacteria which are vital for human health. This study unprecedently reports the mitigation of this challenge through the targeted delivery of antibiotics to a specific intestinal model pathogen using naturally occurring nanoclay. The designed Halloysite nanotubes targeting (HaNTr) system employs intrinsically mesoporous clay particles, functionalized with antibodies against Escherichia coli (E. coli). Loaded with the antibiotic ciprofloxacin (CIP), the HaNTr particles demonstrate enhanced selectivity of their payload in a human microbiome ex vivo system, preserving the composition of non-target populations. Furthermore, the HaNTr system exhibits up to a 10-fold increase in selectivity against E. coli, compared to neat CIP, in a heterogenous culture. This enhanced selectivity is attributed to the sustained and localized release of CIP from the HaNTr particles (≈0.8 ng CIP min−1 mg−1), following their specific binding to target bacteria, as quantitatively measured by high-throughput imaging flow cytometry. Importantly, HaNTr particles are also shown to be biocompatible with Caco-2 cells, mimicking the intestinal epithelium. This work highlights the prominent capability of the HaNTr system in alleviating antibiotic-associated dysbiosis by the targeted delivery of antimicrobials to potentially any microorganism against which the immobilized capture probe can be customized.  相似文献   

15.
    
Gene therapy holds great promise as a biomedicine for treating cancer, viral infection, and recessive gene disorders, while genetic detection has been used for disease diagnosis and prevention. The appropriate carrier is crucial to improve the delivery efficiency of nucleic acids. Although viral and nonviral delivery vectors have been developed, their poor nucleic acid loading efficiency, off-target toxicity, and immunogenicity significantly hamper their use. Metal-organic frameworks (MOFs) have attracted a lot of attention owing to their high surface areas and tunable structures. Recently, nanometric MOFs are shown to be promising nonviral vectors in gene delivery and detection although at an early stage of development. This review focuses on highlighting the current status and promising breakthroughs of MOF use in nucleic acid delivery, including siRNA, miRNA and mRNA delivery, DNA gene delivery and transfection, as well as probes for detection of gene expression. This study will help promote the clinical transformation and application of gene modulation, gene delivery, and detection that use of MOFs can offer.  相似文献   

16.
    
Growing resistance of microorganisms to antibiotics due to their widespread use has led to multiple bacterial infections posing a serious threat to health and human life. Low-frequency ultrasound is one of physical methods for inactivation of pathogenic microbial cells. Application of ultrasound is safe, demonstrates good tissue penetration without significant attenuation of energy, and does not induce microbial resistance. Bactericidal effect of ultrasound is based on acoustic cavitation—the growth and collapse of microbubbles in a liquid medium, resulting in shock waves, shear forces, and microjets which cause irreversible damage and inactivation of microorganisms. The present review combines and analyzes literature data on in vitro and in vivo studies and summarizes works demonstrating the ability of ultrasound, alone or in combination with other methods, to combat pathogenic microorganisms. The results of various studies presented in this review show that low-frequency ultrasound has a noticeable antimicrobial effect on planktonic cells of microorganisms and biofilms. Ultrasound synergistically enhances the effectiveness of other antibacterial agents and activates molecules called sonosensitizers, resulting in the formation of compounds toxic to microbial cells. Ultrasound can also promote local release of antimicrobial drugs from liposomes, as well as from medical implants.  相似文献   

17.
    
Mesoporous silica nanoparticles (MSNs) have been well‐demonstrated as excellent carriers for anticancer drug delivery. Presented here is a cancer‐targeted MSNs drug delivery system that allows the direct fluorescence monitoring of the cellular uptake and localization of theranostic agents in cancer cells. Specifically, the anticancer action mechanisms of RGD peptide‐functionalized MSNs carrying ruthenium polypyridyl complexes (RuPOP@MSNs) are elucidated in detail. RGD peptide surface decoration significantly enhances the cellular uptake of the nanoparticles through receptor‐mediated endocytosis, and increases the selectivity between cancer and normal cells. RuPOP@MSNs exhibits unprecedented enhanced cytotoxicity toward cancer cells overexpressing integrin receptor, which is significantly higher than that of free RuPOP, through induction of apoptosis. The important contribution of extrinsic pathway to cell apoptosis is confirmed by increase in expression levels of death receptors, activation of caspase‐8 and truncation of Bid. The internalized nanoparticles release free RuPOP into the cytoplasm, where they modulate the phosphorylation of p53, AKT, and MAPKs pathways to promote cell apoptosis. Moreover, the strong autofluorescence of RuPOP permits the direct monitoring of drug delivery, and extends the power of theranostics to subcellular level. Taken together, this study provides an effective strategy for the design and development of cancer‐targeted theranostic agents.  相似文献   

18.
    
Extracellular vesicles (EVs) are widely used as natural nanoparticles to deliver various cargos for disease diagnosis and therapy. However, unmodified EVs cannot efficiently transport the cargos to desired sites due to non-specific uptake. Here, a delivery system is designed to display nanobodies against cadherin 17 (CDH17) on the surface of EVs isolated from HEK-293 cells and loaded with dye Indocyanine green (ICG) and/or anti-cancer drug dinitroazetidine derivative RRx-001, a blocker for CD47/ signal regulatory protein alpha (SIRPα) axis. CDH17 is a promising target for gastric cancer (GC) therapy. In this study, ICG loaded in the EVs engineered with CDH17 nanobodies can realize rapid tumor imaging in a CDH17-positive GC model and can produce significant anti-tumor photothermal therapeutic (PTT) effect after irradiation. Meanwhile, PTT effect can induce immunogenic cell death and macrophage polarization from M2 to M1 phenotype. The engineered EVs loaded with RRx-001 can significantly repress GC tumor growth. Finally, dual loading of ICG/RRx-001 in engineered EVs show maximal anti-tumor efficacy in both cancer cell and patient-derived GC models after only single injection. Collectively, CDH17 nanobody-functionalized EVs loaded with ICG and/or RRx-001 hold great promise to image and treat GC by combining fluorescent dye-induced PTT with chemotherapy.  相似文献   

19.
    
Considering the problems of small interfering RNA (siRNA) delivery using traditional viral and nonviral vehicles, a new siRNA delivery system to enhance efficiency and safety needs to be developed. Here human ferritin‐based proteinticles are genetically engineered to simultaneously display various functional peptides on the surface of proteinticles: cationic peptide to capture siRNA, tumor cell targeting and penetrating peptides, and enzymatically cleaved peptide to release siRNA inside tumor cell. In the in vitro treatment of poly‐siRNA‐proteinticle complex, both of the tumor cell targeting and penetrating peptides are important for efficient delivery of siRNA, and the red fluorescent protein (RFP) expression in RFP‐expressing tumor cells is notably suppressed by the delivered siRNA with the complementary sequence to RFP mRNA. It seems that the human ferritin‐based proteinticle is an efficient, stable, and safe tool for siRNA delivery, having a great potential for application to in vivo cancer treatment. The unique feature of proteinticles is that multiple and functional peptides can be simultaneously and evenly placed and also easily switched on the proteinticle surface through a simple genetic modification, which is likely to make proteinticles appropriate for targeted delivery of siRNA to a wide range of cancer cells.  相似文献   

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