The recent success of immunotherapies has highlighted the power of leveraging the immune system in the fight against cancer. In order for most immune‐based therapies to succeed, T cell subsets with the correct tumor‐targeting specificities must be mobilized. When such specificities are lacking, providing the immune system with tumor antigen material for processing and presentation is a common strategy for stimulating antigen‐specific T cell populations. While straightforward in principle, experience has shown that manipulation of the antigen presentation process can be incredibly complex, necessitating sophisticated strategies that are difficult to translate. Herein, the design of a biomimetic nanoparticle platform is reported that can be used to directly stimulate T cells without the need for professional antigen‐presenting cells. The nanoparticles are fabricated using a cell membrane coating derived from cancer cells engineered to express a co‐stimulatory marker. Combined with the peptide epitopes naturally presented on the membrane surface, the final formulation contains the necessary signals to promote tumor antigen‐specific immune responses, priming T cells that can be used to control tumor growth. The reported approach represents an emerging strategy that can be used to develop multiantigenic, personalized cancer immunotherapies.

To improve human immunodeficiency virus (HIV) treatment and prevention, therapeutic strategies that can provide effective and broad-spectrum neutralization against viral infection are highly desirable. Inspired by recent advances of cell-membrane coating technology, herein, plasma membranes of CD4+ T cells are collected and coated onto polymeric cores. The resulting T-cell-membrane-coated nanoparticles (denoted as “TNPs”) inherit T cell surface antigens critical for HIV binding, such as CD4 receptor and CCR5 or CXCR4 coreceptors. The TNPs act as decoys for viral attack and neutralize HIV by diverting the viruses away from their intended host targets. This decoy strategy, which simulates host cell functions for viral neutralization rather than directly suppressing viral replication machinery, has the potential to overcome HIV genetic diversity while not eliciting high selective pressure. In this study, it is demonstrated that TNPs selectively bind with gp120, a key envelope glycoprotein of HIV, and inhibit gp120-induced killing of bystander CD4+ T cells. Furthermore, when added to HIV viruses, TNPs effectively neutralize the viral infection of peripheral mononuclear blood cells and human-monocyte-derived macrophages in a dose-dependent manner. Overall, by leveraging natural T cell functions, TNPs show great potential as a new therapeutic agent against HIV infection.

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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...

Effective endosomal escape after cellular uptake represents a major challenge in the field of nanodelivery, as the majority of drug payloads must localize to subcellular compartments other than the endosomes in order to exert activity. In nature, viruses can readily deliver their genetic material to the cytosol of host cells by triggering membrane fusion after endocytosis. For the influenza A virus, the hemagglutinin (HA) protein found on its surface fuses the viral envelope with the surrounding membrane at endosomal pH values. Biomimetic nanoparticles capable of endosomal escape were fabricated using a membrane coating derived from cells engineered to express HA on their surface. When evaluated in vitro, these virus-mimicking nanoparticles were able to deliver an mRNA payload to the cytosolic compartment of target cells, resulting in the successful expression of the encoded protein. When the mRNA-loaded nanoparticles were administered in vivo, protein expression levels were significantly increased in both local and systemic delivery scenarios. We therefore conclude that utilizing genetic engineering approaches to express viral fusion proteins on the surface of cell membrane-coated nanoparticles is a viable strategy for modulating the intracellular localization of encapsulated cargoes.

Graphical abstract

Effective endosomal escape after cellular uptake represents a major challenge in the field of nanodelivery, as the majority of drug payloads must localize to subcellular compartments other than the endosomes in order to exert activity. In nature, viruses can readily deliver their genetic material to the cytosol of host cells by triggering membrane fusion after endocytosis. For the influenza A virus, the hemagglutinin (HA) protein found on its surface fuses the viral envelope with the surrounding membrane at endosomal pH values. Biomimetic nanoparticles capable of endosomal escape were fabricated using a membrane coating derived from cells engineered to express HA on their surface. When evaluated in vitro, these virus-mimicking nanoparticles were able to deliver an mRNA payload to the cytosolic compartment of target cells, resulting in the successful expression of the encoded protein. When the mRNA-loaded nanoparticles were administered in vivo, protein expression levels were significantly increased in both local and systemic delivery scenarios. We therefore conclude that utilizing genetic engineering approaches to express viral fusion proteins on the surface of cell membrane-coated nanoparticles is a viable strategy for modulating the intracellular localization of encapsulated cargoes.

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