Adoptive cell transfers have emerged as a disruptive approach to treat disease in a manner that is more specific than using small-molecule drugs; however, unlike traditional drugs, cells are living entities that can alter their function in response to environmental cues. In the present study, we report an engineered particle referred to as a “backpack” that can robustly adhere to macrophage surfaces and regulate cellular phenotypes in vivo. Backpacks evade phagocytosis for several days and release cytokines to continuously guide the polarization of macrophages toward antitumor phenotypes. We demonstrate that these antitumor phenotypes are durable, even in the strongly immunosuppressive environment of a murine breast cancer model. Conserved phenotypes led to reduced metastatic burdens and slowed tumor growths compared with those of mice treated with an equal dose of macrophages with free cytokine. Overall, these studies highlight a new pathway to control and maintain phenotypes of adoptive cellular immunotherapies.

The delivery of therapeutics to the brain in an efficient, noninvasive manner continues to be a major unmet need in the field of drug delivery. One significant impediment to brain delivery results from the existence of the physical yet dynamic blood–brain barrier (BBB). Despite the many, often complex strategies that currently exist to breach the BBB, adequate delivery of effective therapeutics from the bloodstream continues to remain quite low. Nanotechnology has emerged as a promising tool for brain delivery, but little is known about the important particle parameters that influence delivery. Here, we synthesized and characterized a library of nanoparticles with distinct properties ranging from size, shape, stiffness, and composition to investigate and identify the key attributes influencing particle uptake and transport for brain delivery. To accomplish this task, an in vitro human BBB model was developed and validated using human cerebral microvascular endothelial cells (hCMEC/D3). Particle uptake and apparent permeability coefficients (P app) were then determined for each particle group. To elucidate the roles of different parameters on particle uptake and transport across the BBB, the predominant mechanisms of endocytosis were also investigated. Our results show that particle composition yielded the greatest impact on penetration across the BBB model. This work lays the foundation and provides new insights into the role of particle parameters on penetration across the BBB.

Biopharmaceuticals have emerged to play a vital role in disease treatment and have shown promise in the rapidly expanding pharmaceutical market due to their high specificity and potency. However, the delivery of these biologics is hindered by various physiological barriers, owing primarily to the poor cell membrane permeability, low stability, and increased size of biologic agents. Since many biological drugs are intended to function by interacting with intracellular targets, their delivery to intracellular targets is of high relevance. In this review, the authors summarize and discuss the use of nanocarriers for intracellular delivery of biopharmaceuticals via endosomal escape and, especially, the routes of direct cytosolic delivery by means including the caveolae‐mediated pathway, contact release, intermembrane transfer, membrane fusion, direct translocation, and membrane disruption. Strategies with high potential for translation are highlighted. Finally, the authors conclude with the clinical translation of promising carriers and future perspectives.

and pluripotent stem cells are in various stages of development for the treatment of cancer, chronic infections, and autoimmune disorders. [9] However, many of these strategies rely on the genetic alteration and expansion of cells, which requires several weeks of preparation. [10] For example, CAR T cell therapies require a preparation time of at least three weeks, which can be prohibitively long for patients with advanced or metastatic cancers. [11,12] Thus, there is a broad interest in engineering functional cells ex vivo in a manner that is rapid, scalable, and agnostic to the therapeutic cell of interest. [10,13] One approach to addressing this challenge is the concurrent delivery of biomolecules through the integration of carried nanoparticles (e.g., "hitchhiking" or "backpack" systems) on the surface of living cells to improve therapeutic potency. [14-19] This strategy has shown promising results in preclinical studies, [20-23] however, the stable attachment of nanoparticles to cell surfaces often relies on interactions that only work for certain cell types in specific particlecell combinations (e.g., electrostatic, hydrophobic, hyaluronan-CD44, and antibody-antigen interactions). [10,24] Moreover, though some methods allow the formation of functional thin films around the cells, such as layer-by-layer (LbL) assemblies or surface-initiated polymerization around cells, [25-27] these techniques Approaches to safely and effectively augment cellular functions without compromising the inherent biological properties of the cells, especially through the integration of biologically labile domains, remain of great interest. Here, a versatile strategy to assemble biologically active nano complexes, including proteins, DNA, mRNA, and even viral carriers, on cellular surfaces to generate a cell-based hybrid system referred to as "Cellnex" is established. This strategy can be used to engineer a wide range of cell types used in adoptive cell transfers, including erythrocytes, macrophages, NK cells, T cells, etc. Erythrocyte nex can enhance the delivery of cargo proteins to the lungs in vivo by 11-fold as compared to the free cargo counterpart. Biomimetic micro fluidic experiments and modeling provided detailed insights into the targeting mechanism. In addition, Macrophage nex is capable of enhancing the therapeutic efficiency of anti-PD-L1 checkpoint inhibitors in vivo. This simple and adaptable approach may offer a platform for the rapid generation of complex cellular systems. Cell-based therapies, comprising administration of living cells to patients for direct therapeutic activities, have experienced remarkable success in the clinic. [1-4] Chimeric antigen receptor (CAR) T cell therapies in particular have led to improved remission rates in patients with multiple myeloma, leukemia, lymphomas, melanoma, cervical cancer, bile duct cancer, and neuroblastoma compared to traditional chemotherapeutic regimens. [5-8] New treatment strategies implementing erythrocytes, macrophages, monocytes, natural killer (NK) cells,

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