Bacteria have distinctive properties that make them ideal for biomedical applications. They can self‐propel, sense their surroundings, and be externally detected. Using bacteria as medical ...therapeutic agents or delivery platforms opens new possibilities for advanced diagnosis and therapies. Nano‐drug delivery platforms have numerous advantages over traditional ones, such as high loading capacity, controlled drug release, and adaptable functionalities. Combining bacteria and nanotechnologies to create therapeutic agents or delivery platforms has gained increasing attention in recent years and shows promise for improved diagnosis and treatment of diseases. In this review, design principles of integrating nanoparticles with bacteria, bacteria‐derived nano‐sized vesicles, and their applications and future in advanced diagnosis and therapeutics are summarized.
Nanoparticles and bacteria integration holds promise for diverse biomedical applications. This review summarizes strategies and design principles to construct effective delivery/therapeutic platforms combining nanoparticles and bacteria, with a focus on emerging disease diagnosis and treatment applications. Furthermore, the microbiota modulation effect of nanoparticles, the challenges, and perspectives are discussed with a highlight on the future development of novel delivery/therapeutic systems.
Abstract The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous diseases. Low-molecular-weight protamine ...(LMWP) as a cell-penetrating peptide possesses distinct advantages including high cell translocation potency, absence of toxicity of peptide itself, and the feasibility as an efficient carrier for delivering therapeutics. Therefore, it was hypothesized that brain delivery of nanoparticles conjugated with LMWP should be efficiently enhanced following intranasal administration. LMWP was functionalized to the surface of PEG-PLA nanoparticles (NP) via a maleimide-mediated covalent binding procedure. Important parameters such as particle size distribution, zeta potential and surface content were determined, which confirmed the conjugation of LMWP to the surface of nanoparticle. Using 16HBE14o- cells as the cell model, LMWP-NP was found to exhibit significantly enhanced cellular accumulation than that of unmodified NP via both lipid raft-mediated endocytosis and direct translocation processes without causing observable cytotoxic effects. Following intranasal administration of coumarin-6-loaded LMWP–NP, the AUC0–8 h of the fluorescent probe detected in the rat cerebrum, cerebellum, olfactory tract and olfactory bulb was found to be 2.03, 2.55, 2.68 and 2.82 folds, respectively, compared to that of coumarin carried by NP. Brain distribution analysis suggested LMWP-NP after intranasal administration could be delivered to the central nervous system along both the olfactory and trigeminal nerves pathways. The findings clearly indicated that the brain delivery of nanoparticles could be greatly facilitated by LMWP and the LMWP-functionalized nanoparticles appears as a effective and safe carrier for nose-to-brain drug delivery in potential diagnostic and therapeutic applications.
Advances in active targeting drug delivery system (DDS) have revolutionized glioma diagnosis and therapy. However, the lack of the sufficient targets on glioma cells and limited penetration ...capability of DDS have significantly compromised the treatment efficacy. In this study, by taking advantages of the abundant extracellular matrix-derived heparan sulfate proteoglycan (HSPG) and enhanced tumor penetration ability mediated by neuropilin-1 (NRP-1) protein, we reported the ATWLPPR and CGKRK peptide dual-decorated nanoparticulate DDS (designated AC-NP) to achieve angiogenic blood vessels and tumor microenvironment dual-targeting effect. The resulted AC-NP displayed the particle size of 123 ± 19.47 nm. Enhanced cellular association of AC-NP was achieved on HUVEC cells and U87MG cells. AC-NP was internalized via caveolin- and lipid raft-mediated mechanism with the involvement of energy and lysosome in HUVEC cells and via caveolin- and lipid raft-mediated pathway with the participation of energy, microtubulin, and lysosome in U87MG cells. After loading with anticancer drug, paclitaxel (PTX), the enhanced apoptosis induction and antiproliferative activity were achieved by AC-NP. Furthermore, in vitro U87MG tumor spheroids assays showed a deeper penetration and an enhanced inhibitory effect against the U87MG tumor spheroids achieved by AC-NP. In vivo animal experiment showed that decoration of AC peptide on the nanoparticulate DDS resulted in extensive accumulation at glioma site and improved anti-glioma efficacy. Collectively, the results suggested that AC-NP holds great promise to serve as an effective tumor blood vessel and tumor microenvironment dual-targeting DDS with enhanced penetration capability, holding great potential in improving anti-glioma efficacy.
ConspectusCells, particularly living cells, serve as natural carriers of bioactive substances. Their inherent low immunogenicity and multifunctionality have garnered significant attention in the ...realm of disease treatment applications, specifically within the domains of cancer immunotherapy and regenerative tissue repair. Nevertheless, several prominent challenges impede their swift translation into clinical applications, including obstacles related to large-scale production feasibility and high utilization costs. To address these issues comprehensively, researchers have proposed the notion of bionic cells that are synthetically generated through chemical or biosynthetic means to emulate cellular functions and behaviors. However, artificial cell strategies encounter difficulties in fully replicating the intricate functionalities exhibited by living cells while also grappling with the complexities associated with design implementation for clinical translation purposes. The convergence of disciplines has facilitated the reform of living cells through a range of approaches, including chemical-, biological-, genetic-, and materials-based methods. These techniques can be employed to impart specific functions to cells or enhance the efficacy of therapy. For example, cells are engineered through gene transduction, surface modifications, endocytosis of drugs as delivery systems, and membrane fusion. The concept of engineered cells presents a promising avenue for enhancing control over living cells, thereby enhancing therapeutic efficacy while concurrently mitigating toxic side effects and ultimately facilitating the realization of precision medicine.In this Account, we present a comprehensive overview of our recent research advancements in the field of engineered cells. Our work involves the application of biological or chemical engineering techniques to manipulate endogenous cells for therapeutics or drug delivery purposes. For instance, to avoid the laborious process of isolating, modifying, and expanding engineered cells in vitro, we proposed the concept of in situ engineered cells. By applying a hydrogel loaded with nanoparticles carrying edited chimeric antigen receptor (CAR) plasmids within the postoperative cavity of glioma, we successfully targeted tumor-associated macrophages for gene editing, leading to effective tumor recurrence inhibition. Furthermore, leveraging platelet's ability to release microparticles upon activation at injury sites, we modified antiprogrammed death 1 (PD-1) antibodies on their surface to suppress postoperative tumor recurrence and provide immunotherapy for inoperable tumors. Similarly, by exploiting bacteria's active tropism toward sites of inflammation and hypoxia, we delivered protein drugs by engineered bacteria to induce cancer cell death through pyroptosis initiation and immunotherapy strategies. In the final section, we summarize our aforementioned research progress while providing an outlook on cancer therapy and the hurdles for clinical translation with potential solutions or future directions based on the concept of engineered cells.ConspectusCells, particularly living cells, serve as natural carriers of bioactive substances. Their inherent low immunogenicity and multifunctionality have garnered significant attention in the realm of disease treatment applications, specifically within the domains of cancer immunotherapy and regenerative tissue repair. Nevertheless, several prominent challenges impede their swift translation into clinical applications, including obstacles related to large-scale production feasibility and high utilization costs. To address these issues comprehensively, researchers have proposed the notion of bionic cells that are synthetically generated through chemical or biosynthetic means to emulate cellular functions and behaviors. However, artificial cell strategies encounter difficulties in fully replicating the intricate functionalities exhibited by living cells while also grappling with the complexities associated with design implementation for clinical translation purposes. The convergence of disciplines has facilitated the reform of living cells through a range of approaches, including chemical-, biological-, genetic-, and materials-based methods. These techniques can be employed to impart specific functions to cells or enhance the efficacy of therapy. For example, cells are engineered through gene transduction, surface modifications, endocytosis of drugs as delivery systems, and membrane fusion. The concept of engineered cells presents a promising avenue for enhancing control over living cells, thereby enhancing therapeutic efficacy while concurrently mitigating toxic side effects and ultimately facilitating the realization of precision medicine.In this Account, we present a comprehensive overview of our recent research advancements in the field of engineered cells. Our work involves the application of biological or chemical engineering techniques to manipulate endogenous cells for therapeutics or drug delivery purposes. For instance, to avoid the laborious process of isolating, modifying, and expanding engineered cells in vitro, we proposed the concept of in situ engineered cells. By applying a hydrogel loaded with nanoparticles carrying edited chimeric antigen receptor (CAR) plasmids within the postoperative cavity of glioma, we successfully targeted tumor-associated macrophages for gene editing, leading to effective tumor recurrence inhibition. Furthermore, leveraging platelet's ability to release microparticles upon activation at injury sites, we modified antiprogrammed death 1 (PD-1) antibodies on their surface to suppress postoperative tumor recurrence and provide immunotherapy for inoperable tumors. Similarly, by exploiting bacteria's active tropism toward sites of inflammation and hypoxia, we delivered protein drugs by engineered bacteria to induce cancer cell death through pyroptosis initiation and immunotherapy strategies. In the final section, we summarize our aforementioned research progress while providing an outlook on cancer therapy and the hurdles for clinical translation with potential solutions or future directions based on the concept of engineered cells.
Immunotherapy strategies that use cell‐based delivery systems have sparked much interest in the treatment of malignancies, owing to their high biocompatibility, excellent tumor targeting capability, ...and unique biofunctionalities in the tumor growth process. A variety of design principles for cell‐based immunotherapy, including cell surface decoration, cell membrane coating, cell encapsulation, genetically engineered cell, and cell‐derived exosomes, give cancer immunotherapy great potential to improve therapeutic efficacy and reduce adverse effects. However, the treatment efficacy of cell‐based delivery methods for immunotherapy is still limited, and practical uses are hampered due to complex physiological and immunological obstacles, such as physical barriers to immune infiltration, immunosuppressive tumor microenvironment, upregulation of immunosuppressive pathways, and metabolic restriction. In this review, we present an overview of the design principles of cell‐based delivery systems in cancer immunotherapy to maximize the therapeutic impact, along with anatomical, metabolic, and immunological impediments in using cell‐based immunotherapy to treat cancer. Following that, a summary of novel delivery strategies that have been created to overcome these obstacles to cell‐based immunotherapeutic delivery systems is provided. Also, the obstacles and prospects of next‐step development of cell‐based delivery systems for cancer immunotherapy are concluded in the end.
This review covers the design of cell‐based delivery systems for cancer immunotherapy, as well as the significant challenges limiting the efficacy of cell‐based immunotherapy and summarizes recent advances in overcoming those barriers to improve cancer treatment outcomes.
Abstract Nanotechnology plays a unique instrumental role in the revolutionary development of brain-specific drug delivery, imaging, and diagnosis, but is highly limited by the existence of ...blood–brain barrier (BBB). In this study, microbubble-enhanced unfocused ultrasound (MEUUS) was developed as an approach to mediate an extensive brain delivery of poly (ethylene glycol) – poly (lactic acid) (PEG–PLA) nanoparticles. Following the MEUUS treatment, the nanoparticles signals were found to penetrate through the vascular walls and distributed deeply into the parenchyma at a significantly higher level (more than 250%) than those of the non-MEUUS treated control. Such effect was reversible and dependent on nanoparticles injection timing, sonication mode and mechanical index. Together with the transmission electron microscopy analysis, the increased brain accumulation of nanoparticles was claimed to be largely mediated by an ultrasound-induced stable cavitation of the microbubble which resulted in mechanical stretching of the vessel wall and consequently induced cellular transcytosis of the nanoparticles. The MEUUS technique was also used to facilitate the brain delivery of PEG–PLA nanoparticles functionalized with amyloid beta-specific antibody 6E10 for enabling the recognition of the hallmarks of Alzheimer's disease that widely distributed in the brain. No erythrocytes extravasation and other visible damages in the brain were detected following the MEUUS treatment. These findings together indicated that unfocused ultrasound with the aid of microbubble could effectively improve the brain delivery of nanoparticles, and this approach might serve as a safe and flexible platform for the potential application of nanoparticles in the diagnosis and therapy of brain diseases.
Conspectus Cell therapy has become a momentum-gathering treatment strategy for a variety of diseases, including cancer, diabetes, hemophilia, and cardiomyopathy. However, clinical applications of ...conventional cell therapies have often been compromised by rapid decline in viability and function of the transplanted cells due to host recognition and subsequent foreign body rejection. Along this line, cell engineering technologies such as cell encapsulation within microcapsules and immobilization in porous scaffolds have been implemented to address the immunosuppression concerns. As a recent emerging research topic, drawing inspiration from the ways that natural cells interact with the body has opened new avenues for cell engineering, such as direct modification of whole cells with synthetic materials and “top-down” integration of biological membranes with micro/nanomaterials, which aim to alleviate immune response while harnessing the complex biological functions of cells. In this Account, we summarize our recent contribution to the field of cell engineering methodologies, with which we have demonstrated their promising applications for cancer immunotherapy, targeted drug delivery, and blood glucose regulation. For example, inspired by the inherent ability of platelets to accumulate at wound sites and interact with circulating tumor cells, we exploited a targeted checkpoint antibody delivery strategy for treatment of postsurgical cancer recurrence and metastatic spread by covalent binding of platelets’ cell surfaces with a monoclonal antibody against programmed-death ligand 1 (aPDL1). Without interfering with the platelets’ surgical-site homing property, the conjugated aPDL1 could be triggered to release in the form of microparticles after in situ activation. As an extension, we then engineered the platelet membrane to cloak nanoparticles for anticancer drug delivery, mimicking the targeting capability of the source cells while possessing prolonged circulation lifetime and insignificant immunogenicity. At the same time, we also found that the subcellular compartment membrane-derived particulates exhibited high specificity toward homotypic cells, by which enhanced intracellular drug delivery was achieved. Moreover, by taking advantage of the reversible interaction between glucose-derivative-modified insulin and the red blood cell membrane, we constructed a glucose-responsive smart insulin delivery system for long-term maintenance of blood glucose levels within a normal range. Recently, by virtue of painless microneedle patches as convenient cell engineering platforms, a minimally invasive intradermal antitumor vaccine was invented by integrating whole-tumor lysis into near-infrared light-illuminated microneedle patches. The microneedle patches also showed promise in combining with conventional cell encapsulation techniques, by which an externally positioned β-cell engineering strategy was proposed for diabetes treatment. The results presented in this Account demonstrate distinct approaches to the development and application of cell engineering strategies for drug delivery.
Combination chemotherapy is widely exploited for enhanced cancer treatment in the clinic. However, the traditional cocktail administration of combination regimens often suffers from varying ...pharmacokinetics among different drugs. The emergence of nanotechnology offers an unparalleled opportunity for developing advanced combination drug delivery strategies with the ability to encapsulate various drugs simultaneously and unify the pharmacokinetics of each drug. This review surveys the most recent advances in combination delivery of multiple small molecule chemotherapeutics using nanocarriers. The mechanisms underlying combination chemotherapy, including the synergistic, additive and potentiation effects, are also discussed with typical examples. We further highlight the sequential and site-specific co-delivery strategies, which provide new guidelines for development of programmable combination drug delivery systems. Clinical outlook and challenges are also discussed in the end.
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Biodegradable polyester nanoparticles have now attracted growing interest as promising drug delivery system. However, a fundamental understanding about its cellular transport as well as the influence ...by the polymeric architecture is still lack, which remains a significant obstacle to optimal nanocarrier design. In this work, using Caco-2 cell model, we characterized the cellular transport pathway of pegylated polyester nanoparticles and determined the effect of polymer architecture including PEG chain length and core material on its cellular interaction and transcellular transport. The nanoparticles were found to undergo an energy-dependent, lipid raft-mediated, but caveolae-independent endocytosis. PEG chain length (from 2000 to 5000Da) and core material (PLA/PLGA) hardly affected the cellular interaction and the intracellular itinerary of the nanoparticles. However, in the case of transcellular transport, the maximal transcellular transport efficiency for its payload was achieved by the PEG5000-PLA40000 nanoparticles which present higher drug loading capacity and slower drug release. The findings here revealed the cellular interaction mechanism of pegylated polyester nanoparticles and provided evidence for the role of polymer architectures in modulating the transcellular permeability of the agents loaded by the nanoparticles, and would be helpful in improving carrier design to enhance drug delivery.
Platelet for drug delivery Lu, Yifei; Hu, Quanyin; Jiang, Chen ...
Current opinion in biotechnology,
August 2019, 2019-08-00, 20190801, Letnik:
58
Journal Article
Recenzirano
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Platelets play a vital physiological role in hemostasis, inflammation and tissue regeneration, which are associated with wound healing as well as cancer development and metastasis. ...These years, a variety of platelet-mediated drug delivery approaches have been developed due to their unique properties, such as quick replenishment and site-specific activation/adhesion. In this Current Opinion, focuses are put on strategies leveraging the physiological functions of platelets for the design of drug delivery systems, including platelet engineering, platelet hitchhiking, membrane coating, synthetic platelet fabrication and platelet-triggered drug release for different applications.
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