Abstract Transcellular transport is essential for transmucosal and plasma-to-tissue drug delivery by nanoparticles, whereas its fundamental pathways have not been fully clarified. In this study, an ...in-depth investigation was conducted into the intracellular itinerary and the transcytosis pathway of wheat germ agglutinin-functionalized nanoparticles (WGA-NP) with various polymer architectures in the Caco-2 cell model. GFP-Rabs, Rab4, Rab5, Rab7, Rab11, GTPases served as key regulators of vesicular transport, and their mutants were transfected to Caco-2 cells respectively to determine the cellular itinerary of WGA-NP and the role of Rabs therein. Transcytosis inhibition experiments indicated that transcellular transport of WGA-NP (PEG3000 -PLA40000 formulation) happened in a cytoskeleton-dependent manner and majorly by means of clathrin-mediated mechanism. Intracellular transport, especially the endolysosome pathway was found largely contribute to the transcytosis of WGA-NP. WGA-NP with shorter surface PEG length (2000) resulted in higher cellular association and more colocalization with the clathrin-mediated transport pathway, while that with longer surface PEG length (5000) avoided the clathrin-mediated transport pathway but achieved higher transcytosis after 4 h incubation. WGA-NP with PLGA as the core materials obtained elevated lysosome escape and enhanced transcytosis after 2 h incubation. These findings provided important evidence for the role of polymer architectures in modulating cellular transport of functionalized nanocarriers, and would be helpful in improving carrier design to enhance drug delivery.
Physiological characteristics of diseases bring about both challenges and opportunities for targeted drug delivery. Various drug delivery platforms have been devised ranging from macro- to micro- and ...further into the nanoscopic scale in the past decades. Recently, the favorable physicochemical properties of nanomaterials, including long circulation, robust tissue and cell penetration attract broad interest, leading to extensive studies for therapeutic benefits. Accumulated knowledge about the physiological barriers that affect the in vivo fate of nanomedicine has led to more rational guidelines for tailoring the nanocarriers, such as size, shape, charge, and surface ligands. Meanwhile, progresses in material chemistry and molecular pharmaceutics generate a panel of physiological stimuli-responsive modules that are equipped into the formulations to prepare "smart" drug delivery systems. The capability of harnessing physiological traits of diseased tissues to control the accumulation of or drug release from nanomedicine has further improved the controlled drug release profiles with a precise manner. Successful clinical translation of a few nano-formulations has excited the collaborative efforts from the research community, pharmaceutical industry, and the public towards a promising future of smart drug delivery.
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The relay delivery strategy is a two-step targeting approach based on two distinct modules in which the first step with an initiator is to artificially create a target/environment ...which can be targeted by the follow-up effector. This relay delivery concept creates opportunities to amplify existing or create new targeted signals through deploying initiators to enhance the accumulation efficiency of the following effector at the disease site. As the “live” medicines, cell-based therapeutics possess inherent tissue/cell homing abilities and favorable feasibility of biological and chemical modifications, endowing them the great potential in specifically interacting with diverse biological environments. All these unique capabilities make cellular products great candidates that can serve as either initiators or effectors for relay delivery strategies. In this review, we survey recent advances in relay delivery strategies with a specific focus on the roles of various cells in developing relay delivery systems.
Bacteria are one of the main groups of organisms, which dynamically and closely participate in human health and disease development. With the integration of chemical biotechnology, bacteria have been ...utilized as an emerging delivery system for various biomedical applications. Given the unique features of bacteria such as their intrinsic biocompatibility and motility, bacteria‐based delivery systems have drawn wide interest in the diagnosis and treatment of various diseases, including cancer, infectious diseases, kidney failure, and hyperammonemia. Notably, at the interface of chemical biotechnology and bacteria, many research opportunities have been initiated, opening a promising frontier in biomedical application. Herein, the current synergy of chemical biotechnology and bacteria, the design principles for bacteria‐based delivery systems, the microbial modulation, and the clinical translation are reviewed, with a special focus on the emerging advances in diagnosis and therapy.
Bacteria‐based delivery systems are versatile platforms developed for diagnosis and therapy. The fundamentals and design principles of chemically and biologically engineered bacteria delivery systems are summarized, and recent advances of their application in emerging diagnosis and advanced therapy are highlighted, including microbial modulation and clinical translation, which have offered tremendous promise for various disease treatments.
Self-regulated micro/nano drug delivery devices are smart drug delivery platforms that can sense the changes of physiological indexes and adjust their own properties or performance in response to the ...stimuli, especially the internal biological signals. Due to the great convenience and treatment outcomes they can bring to the patients who are suffering from chronic diseases, self-regulated drug delivery devices have drawn wide research interests. Armed with advanced micro/nanotechnology and mechanical/electronic fabrication technique as well as a better understanding of physiological characteristics and biomarkers, numerous breakthroughs have been made in developing closed-loop regulating micro/nanodevices. Here we survey the current platforms for self-regulated drug delivery, introduce their applications in different diseases and summarize strategies to design self-regulated micro/nano drug delivery devices.
This review mainly summarized the recent advances in self-regulated micro/nano drug delivery devices for intelligent diagnosis and therapeutics. The designing principles and the architecture of the self-regulated devices for intelligent diagnosis and therapeutics were discussed. The current limitations and challenges for devices that allow closed-loop regulation were examined and the future orientation and prospect were envisioned. Display omitted
•Self-regulated drug delivery devices based on nanotechnology and micro-fabrication hold great promises in the clinic.•The designing principles, platforms and architectures of the advanced closed-loop regulated devices are reviewed.•Challenges for the clinical application and future development directions of the self-regulated devices are discussed.•Self-regulated devices are the ideal candidates to realize point-of-care diagnosis and on-demand therapy.
Immunotherapy is leading a paradigm shift in the treatment of various diseases, including tumors, auto‐immune diseases, and infectious diseases. However, the limited response rate and systemic side ...effects significantly impede the clinical applications of immunotherapy. As natural carriers for proteins and molecules, cells with low immunogenicity and toxicity have attracted considerable attention for biomedical applications and have achieved encouraging progress especially in immunotherapy. The convergence of multiple disciplines has equipped cell‐based delivery systems with control over their spatiotemporal distribution to enhance treatment efficacy and reduce side effects. Here, an overview of the fundamentals and design principles of cell‐based delivery systems followed by a perspective that includes the most recent advances of various cells as delivery carriers, with a special focus on the implications of cell‐based delivery systems for immunotherapy is offered.
This review summarizes the recent advances in cell‐based delivery systems and their emerging applications with a focus on immunotherapy for cancers, infectious diseases, and auto‐immune diseases. Specifically, the designing principles, clinical limitations, and future directions of cell‐based delivery systems for immunotherapy are discussed, which will inspire interdisciplinary integration and collaboration to develop the next generation of bioinspired delivery systems.
Macrophages, as one of the most abundant tumor-infiltrating cells, play an important role in tumor development and metastasis. The frequency and polarization of tumor-associated macrophages (TAMs) ...correlate with disease progression, tumor metastasis, and resistance to various treatments. Pro-inflammatory M1 macrophages hold the potential to engulf tumor cells. In contrast, anti-inflammatory M2 macrophages, which are predominantly present in tumors, potentiate tumor progression and immune escape. Targeting macrophages to modulate the tumor immune microenvironment can ameliorate the tumor-associated immunosuppression and elicit an anti-tumor immune response. Strategies to repolarize TAMs, deplete TAMs, and block inhibitory signaling hold great potential in tumor therapy. Besides, biomimetic carriers based on macrophages have been extensively explored to prolong circulation, enhance tumor-targeted delivery, and reduce the immunogenicity of therapeutics to augment therapeutic efficacy. Moreover, the genetic engineering of macrophages with chimeric antigen receptor (CAR) allows them to recognize tumor antigens and perform tumor cell-specific phagocytosis. These strategies will expand the toolkit for treating tumors, especially for solid tumors, drug-resistant tumors, and metastatic tumors. Herein, we introduce the role of macrophages in tumor progression, summarize the recent advances in macrophage-centered anticancer therapy, and discuss their challenges as well as future applications.
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Patients with advanced melanoma that is of low tumor‐associated antigen (TAA) expression often respond poorly to PD‐1/PD‐L1 blockade therapy. Epigenetic modulators, such as hypomethylation agents ...(HMAs), can enhance the antitumor immune response by inducing TAA expression. Here, a dual bioresponsive gel depot that can respond to the acidic pH and reactive oxygen species (ROS) within the tumor microenvironment (TME) for codelivery of anti‐PD1 antibody (aPD1) and Zebularine (Zeb), an HMA, is engineered. aPD1 is first loaded into pH‐sensitive calcium carbonate nanoparticles (CaCO3 NPs), which are then encapsulated in the ROS‐responsive hydrogel together with Zeb (Zeb‐aPD1‐NPs‐Gel). It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, and also plays roles in reversing immunosuppressive TME, which contributes to inhibiting the tumor growth and prolonging the survival time of B16F10‐melanoma‐bearing mice.
A dual bioresponsive drug delivery depot is engineered, which can respond to the acidic pH and reactive oxygen species within the tumor microenvironment (TME), for codelivery of anti‐PD1 antibody and Zebularine, an epigenetic modulator. It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, reverses immunosuppressive TME, and enhances the antitumor immune response.
Chimeric antigen receptor (CAR)‐redirected T lymphocytes (CAR T cells) show modest therapeutic efficacy in solid tumors. The desmoplastic structure of the tumor and the immunosuppressive tumor ...microenvironment usually account for the reduced efficacy of CAR T cells in solid tumors. Mild hyperthermia of the tumor reduces its compact structure and interstitial fluid pressure, increases blood perfusion, releases antigens, and promotes the recruitment of endogenous immune cells. Therefore, the combination of mild hyperthermia with the adoptive transfer of CAR T cells can potentially increase the therapeutic index of these cells in solid tumors. It is found that the chondroitin sulfate proteoglycan‐4 (CSPG4)‐specific CAR T cells infused in Nod scid gamma mice engrafted with the human melanoma WM115 cell line have superior antitumor activity after photothermal ablation of the tumor. The findings suggest that photothermal therapy facilitates the accumulation and effector function of CAR T cells within solid tumors.
Photothermal ablation of tumors is demonstrated to promote the therapeutic efficacy of chimeric antigen receptor (CAR) T cells. Mild hyperthermia can promote direct tumor cell killing, partially disrupt the extracellular matrix, decrease the interstitial fluid pressure, and increase local blood perfusion. All these modifications caused by photothermal therapy ultimately promote the infiltration and antitumor effects of adoptively transferred CAR T cells.
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