Biomimetic nanoparticles aim to effectively emulate the behavior of either cells or exosomes. Leukocyte-based biomimetic nanoparticles, for instance, incorporate cell membrane proteins to transfer the natural tropism of leukocytes to the final delivery platform. However, tuning the protein integration can affect the in vivo behavior of these nanoparticles and alter their efficacy. Here we show that, while increasing the protein:lipid ratio to a maximum of 1:20 (w/w) maintained the nanoparticle’s structural properties, increasing protein content resulted in improved targeting of inflamed endothelium in two different animal models. Our combined use of a microfluidic, bottom-up approach and tuning of a key synthesis parameter enabled the synthesis of reproducible, enhanced biomimetic nanoparticles that have the potential to improve the treatment of inflammatory-based conditions through targeted nanodelivery.

Traumatic brain injury (TBI) triggers both central and peripheral inflammatory responses. Existing pharmacological drugs are unable to effectively and quickly target the brain inflamed regions, setting up a major roadblock towards effective brain trauma treatments. Nanoparticles (NPs) have been used in multiple diseases as drug delivery tools with remarkable success due to their rapid diffusion and specificity in the target organ. Here, leukocyte-based biomimetic NPs are fabricated as a theranostic tool to directly access inflamed regions in a TBI mouse model. This NP systemic delivery is visualized using advanced in vivo imaging techniques, including intravital microscopy and in vivo imaging system. The results demonstrate selective targeting of NPs to the injured brain and increased NPs accumulation among the peripheral organs 24 h after TBI. Interestingly, increased microglial proliferation, decreased macrophage infiltration, and reduced brain lesion following the NPs treatments compared to sham vehicle-treated mice are also found. In summary, the results suggest that NPs represent a promising future theranostic tool for TBI treatment.

Ponatinib (Pon) is a multi-tyrosine kinase inhibitor that demonstrated high efficiency for treating cancer. However, severe side effects caused by Pon off-targeting effects prevent its extensive use. Using our understanding into the mechanisms by which Pon is transported by bovine serum albumin in the blood, we have successfully encapsulated Pon into a biomimetic nanoparticle (NP). This lipid NP (i.e., “leukosomes”) incorporates membrane proteins purified from activated leukocytes that enable immune evasion, and enhanced targeting of inflamed endothelium NPs have been characterized for their size, charge, and encapsulation efficiency. Membrane proteins enriched on the NP surface enabled modulation of Pon release. These NP formulations showed promising dose–response results on two different murine osteosarcoma cell lines, F420 and RF379. Our results indicate that our fabrication method is reproducible, nonuser-dependent, efficient in loading Pon, and applicable toward repurposing numerous therapeutic agents previously shelved due to toxicity profiles.

Nanovesicles (NVs) are emerging as innovative, theranostic tools for cargo delivery. Recently, surface engineering of NVs with membrane proteins from specific cell types has been shown to improve the biocompatibility of NVs and enable the integration of functional attributes. However, this type of biomimetic approach has not yet been explored using human neural cells for applications within the nervous system. Here, this paper optimizes and validates the scalable and reproducible production of two types of neuron-targeting NVs, each with a distinct lipid formulation backbone suited to potential therapeutic cargo, by integrating membrane proteins that are unbiasedly sourced from human pluripotent stem-cell-derived neurons. The results establish that both endogenous and genetically engineered cell-derived proteins effectively transfer to NVs without disruption of their physicochemical properties. NVs with neuron-derived membrane proteins exhibit enhanced neuronal association and uptake compared to bare NVs. Viability of 3D neural sphere cultures is not disrupted by treatment, which verifies the utility of organoid-based approaches as NV testing platforms. Finally, these results confirm cellular association and uptake of the biomimetic humanized NVs to neurons within rodent cranial nerves. In summary, the customizable NVs reported here enable next-generation functionalized theranostics aimed to promote neuroregeneration.

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Humanized Biomimetic Nanovesicles In article number 2101437, Assaf Zinger, Francesca Taraballi, Robert Krencik, and co‐workers optimize and validate the scalable production of neuron‐targeting biomimetic nanovesicles (NV) with distinct lipid backbones suited to potential therapeutic cargo by integrating membrane proteins from human pluripotent stem cell‐derived neurons. NVs with neuronderived membrane proteins exhibit enhanced neuronal association and uptake compared to bare NVs. These customizable NVs enable next‐generation functionalized theranostics for neurodegeneration.

The pro‐inflammatory microenvironment that contributes to atherosclerotic plaque progression is sustained by M1 macrophages. Metabolic reprogramming toward heightened glycolysis accompanies M1 macrophage polarization, with approaches aimed at lessening glycolytic metabolism in macrophages standing to impact disease progression. The objective is to decrease the inflammatory response in atherosclerotic lesions by inducing favorable metabolic phenotypes in macrophages using an innovative mitochondrial transplantation strategy. The hypothesis is that delivery of mitochondria, functionalized with a dextran and triphenylphosphonium (Dextran‐TPP) polymer conjugate for enhanced cellular transplantation, to atherosclerotic plaques properly regulates M1 macrophage bioenergetics, attenuating inflammatory processes and preventing plaque progression. Dextran‐TPP mitochondria transplantation to M1 macrophages has profound effects on cell bioenergetics, resulting in increased oxygen consumption rate and reduced glycolytic flux that coincides with a decreased inflammatory response. Upon intravenous delivery to ApoE−/− mice fed a high fat diet, Dextran‐TPP mitochondria accumulate in aortic plaques and co‐localize with macrophages. Importantly, Dextran‐TPP mitochondria treatment reduces the plaque burden in ApoE−/− mice, improving cholesterol levels, and ameliorating hepatic steatosis and inflammation. Findings highlight Dextran‐TPP mitochondria as a novel biological particle for the treatment of atherosclerosis, underlining the potential for macrophage metabolic regulation as a therapy in other diseases.

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