Infections caused by multidrug-resistant gram-negative bacteria have emerged as a major threat to public health worldwide. The high mortality and prevalence, along with the slow pace of new antibiotic discovery, highlight the necessity for new disease management paradigms. Here, we report on the development of a multiantigenic nanotoxoid vaccine based on macrophage membrane-coated nanoparticles for eliciting potent immunity against pathogenic Pseudomonas aeruginosa. The design of this biomimetic nanovaccine leverages the specific role of macrophages in clearing pathogens and their natural affinity for various virulence factors secreted by the bacteria. It is demonstrated that the macrophage nanotoxoid is able to display a wide range of P. aeruginosa antigens, and the safety of the formulation is confirmed both in vitro and in vivo. When used to vaccinate mice via different administration routes, the nanotoxoid is capable of eliciting strong humoral immune responses that translate into enhanced protection against live bacterial infection in a pneumonia model. Overall, the work presented here provides new insights into the design of safe, multiantigenic antivirulence vaccines using biomimetic nanotechnology and the application of these nanovaccines towards the prevention of difficult-to-treat gram-negative infections.
immunotherapy is a powerful tactic that can synergistically amplify efficacy by addressing tumor immunosuppression from multiple angles. [7] Overall, combinatorial approaches hold great promise for expanding the utility of immunotherapies across a wider range of patients.Microrobotic platforms, with their ability to actively deliver a diverse range of cargoes, have garnered significant attention over the past decade given their potential to be used for biomedical applications. [8][9][10][11][12][13][14] Compared with traditional delivery systems that rely on passive transport, microrobots utilize various actuation mechanisms to achieve active delivery that can more rapidly or more specifically localize a payload to a desired target. [15][16][17] These systems can also be designed with different biocompatible materials, such as magnesium (Mg) or zinc, to take advantage of the body's natural fluids for propulsion. [18][19][20] Recently, it has been shown that surface functionalization of micromotors can be readily achieved using cell membrane coating technology, [21][22][23] enabling the resulting biomimetic construct to more effectively interface with its surroundings. [24,25] Despite the numerous advantages of microrobots, their use for in vivo applications is still in its infancy. [8,26] Thus far, the majority of studies have focused on the gastrointestinal tract, where microrobots have been used for detoxification, drug delivery, and immune modulation. [27] In order to push the microrobotics field forward and to expand their clinical utility, the identification of novel areas in which these platforms can excel is imperative.Here, we report the development of a microrobot-based strategy that combines tissue disruption and biological stimulation at a tumor site toward enhanced cancer immunotherapy. Specifically, we utilized a Mg-based micromotor system that can interact with aqueous media to generate a reaction within a solid tumor, resulting in the disruption of the surrounding tumor tissue (Figure 1a). The compromised cancer cells could then act as a source of tumor antigens that were phagocytosed by local antigen-presenting cells to train the immune system. [28][29][30] To enhance their immune recruitment capability, the micromotors were loaded with bacteria-derived outer membrane vesicles (OMVs), [31] which contain a range of immunostimulatory molecules that have been leveraged for cancer treatment. [32][33][34] When administered intratumorally, the OMV-loadedThe combination of immunotherapy with other forms of treatment is an emerging strategy for boosting antitumor responses. By combining multiple modes of action, these combinatorial therapies can improve clinical outcomes through unique synergisms. Here, a microrobot-based strategy that integrates tumor tissue disruption with biological stimulation is shown for cancer immunotherapy. The microrobot is fabricated by loading bacterial outer membrane vesicles onto a self-propelling micromotor, which can react with water to generate a propulsion force. When adm...
Cancer vaccines are promising treatments to prevent relapse after chemotherapy in acute myeloid leukemia (AML) patients, particularly for those who cannot tolerate intensive consolidation therapies. Here, we report the development of an AML cell membrane-coated nanoparticle (AMCNP) vaccine platform, in which immune-stimulatory adjuvant-loaded nanoparticles are coated with leukemic cell membrane material. This AMCNP vaccination strategy stimulates leukemia-specific immune responses by co-delivering membrane-associated antigens along with adjuvants to antigen-presenting cells. To demonstrate that this AMCNP vaccine enhances leukemia-specific antigen presentation and T cell responses, we modified a murine AML cell line to express membrane-bound chicken ovalbumin as a model antigen. AMCNPs were efficiently acquired by antigen-presenting cells in vitro and in vivo and stimulated antigen cross-presentation. Vaccination with AMCNPs significantly enhanced antigen-specific T cell expansion and effector function compared with control vaccines. Prophylactic vaccination with AMCNPs enhanced cellular immunity and protected against AML challenge. Moreover, in an AML post-remission vaccination model, AMCNP vaccination significantly enhanced survival in comparison to vaccination with whole leukemia cell lysates. Collectively, AMCNPs retained AML-specific antigens, elicited enhanced antigen-specific immune responses, and provided therapeutic benefit against AML challenge.
There is an unmet need for novel and efficacious therapeutics for regenerating injured articular cartilage in progressive osteoarthritis (OA) and/or trauma. Mesenchymal stem cells (MSCs) are particularly promising for their chondrogenic differentiation, local healing environment modulation, and tissue- and organism-specific activity; however, despite early in vivo success, MSCs require further investigation in highly-translatable models prior to disseminated clinical usage. Large animal models, such as canine, porcine, ruminant, and equine models, are particularly valuable for studying allogenic and xenogenic human MSCs in a human-like osteochondral microenvironment, and thus play a critical role in identifying promising approaches for subsequent clinical investigation. In this mini-review, we focus on [1] considerations for MSC-harnessing studies in each large animal model, [2] source tissues and organisms of MSCs for large animal studies, and [3] tissue engineering strategies for optimizing MSC-based cartilage regeneration in large animal models, with a focus on research published within the last 5 years. We also highlight the dearth of standard assessments and protocols regarding several crucial aspects of MSC-harnessing cartilage regeneration in large animal models, and call for further research to maximize the translatability of future MSC findings.
Atherosclerosis is a chronic inflammatory vascular disease and one of the leading causes of death worldwide. Macrophages play an important role in atherosclerosis in the inflammatory response, cell-cell communications, plaque growth, and plaque rupture in atherosclerotic lesions. Here we review the sources, functions, and complex phenotypes of macrophages in the progression of atherosclerotic, and discuss the recent approaches in modulating macrophage autophagy and phenotypic transformation for atherosclerosis treatment. We then focus on the drug delivery strategies that target macrophages or use macrophage membrane-coated particles to deliver therapeutics to the lesion sites. These biomaterial-based approaches to target, modulate, or engineer macrophages have broad applications for disease therapies and tissue regeneration.
The migration of cancer cell groups is highly dependent on the chemical and physical guidance cues provided by the tumor stroma, which polarize cell collectives and enable their coordinated movement. For example, macrophages attracted by cancer cells can stimulate the multicellular streaming of tumor cells. [7] Moreover, activated fibroblasts in tumor stroma exert forces on cancer cells [8] and create tracks [9] in extracellular matrix (ECM) or align collagen fibers, [10] which promote efficient directional migration of groups of cancer cells along these features. The movement of cohesive multicellular groups is generally led by an invasive leader cell, which creates a path and sets the direction of migration for non-invasive follower cells in the group. [11] Once the groups of cancer cells invade the vasculature, they can dynamically reorganize and adjust their geometries to pass even through narrow blood vessels. [12] These multicellular groups, also known as circulating tumor cell clusters (CTCCs), can contain between 4 -100 cells. [12] However, CTCCs found in the bloodstream of cancer patients are not composed solely of cancer cells and may also contain mesenchymal cells, endothelial cells, and/or immune cells. [13] Clusters of mesenchymal cells with cancer cells have been detected in the peripheral blood of patients with metastatic breast cancer but not in the blood of healthy donors. The presence of circulating CAFs in the blood was confirmed in 88% of patients with metastatic disease and only in 23% of patients with localized breast cancer. [14] Similarly, increased numbers of circulating mesenchymal cells correlated with a worse prognosis and a lower probability of survival in metastatic patients. [15] The importance of co-traveling mesenchymal/ stromal cells in the metastatic process is also supported by observations that up to 86% of carcinoma cells that spread to the lungs were accompanied by primary tumor stroma-derived cells; in the majority of cases, these cells stained positive for smooth muscle α-actin (α-SMA) but only 28% cases stained positive for F4/80, a macrophage marker. [16] When the tumor stromal cells were partially depleted, the number of metastases significantly decreased.While mesenchymal stromal cells (MSCs) are known to be recruited to damaged or inflamed tissue, where they promote tissue regeneration, MSCs are also attracted to tumor sites. [17][18][19] Currently, without lineage tracing experiments, it is difficult to Cell clusters that collectively migrate from primary tumors appear to be far more potent in forming distant metastases than single cancer cells. A better understanding of the collective cell migration phenomenon and the involvement of various cell types during this process is needed. Here, an in vitro platform based on inverted-pyramidal microwells to follow and quantify the collective migration of hundreds of tumor cell clusters at once is developed. These results indicate that mesenchymal stromal cells (MSCs) or cancer-associated fibroblasts (CAFs) in the heterotypi...
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