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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.

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.

Rationale: Through localized delivery of rapamycin via a biomimetic drug delivery system, it is possible to reduce vascular inflammation and thus the progression of vascular disease. Objective: Use biomimetic nanoparticles to deliver rapamycin to the vessel wall to reduce inflammation in an in vivo model of atherosclerosis after a short dosing schedule. Methods and Results: Biomimetic nanoparticles (leukosomes) were synthesized using membrane proteins purified from activated J774 macrophages. Rapamycin-loaded nanoparticles were characterized using dynamic light scattering and were found to have a diameter of 108±2.3 nm, a surface charge of −15.4±14.4 mV, and a polydispersity index of 0.11 +/ 0.2. For in vivo studies, ApoE −/− mice were fed a high-fat diet for 12 weeks. Mice were injected with either PBS, free rapamycin (5 mg/kg), or rapamycin-loaded leukosomes (Leuko-Rapa; 5 mg/kg) once daily for 7 days. In mice treated with Leuko-Rapa, flow cytometry of disaggregated aortic tissue revealed fewer proliferating macrophages in the aorta (15.6±9.79 %) compared with untreated mice (30.2±13.34 %) and rapamycin alone (26.8±9.87 %). Decreased macrophage proliferation correlated with decreased levels of MCP (monocyte chemoattractant protein)-1 and IL (interleukin)-b1 in mice treated with Leuko-Rapa. Furthermore, Leuko-Rapa–treated mice also displayed significantly decreased MMP (matrix metalloproteinases) activity in the aorta (mean difference 2554±363.9, P =9.95122×10 −6 ). No significant changes in metabolic or inflammation markers observed in liver metabolic assays. Histological analysis showed improvements in lung morphology, with no alterations in heart, spleen, lung, or liver in Leuko-Rapa–treated mice. Conclusions: We showed that our biomimetic nanoparticles showed a decrease in proliferating macrophage population that was accompanied by the reduction of key proinflammatory cytokines and changes in plaque morphology. This proof-of-concept showed that our platform was capable of suppressing macrophage proliferation within the aorta after a short dosing schedule (7 days) and with a favorable toxicity profile. This treatment could be a promising intervention for the acute stabilization of late-stage plaques.

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. [Image: see text]

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., Membrane proteins are extracted from either human pluripotent stem cells or differentiated neurons and combined with lipids to synthesize biomimetic nanovesicles (NVs). Neural targeting of NVs can be evaluated both in vitro using monolayer cultures and 3D organoids and in vivo by direct injection of NVs into murine trigeminal ganglions.

We previously developed novel liposomal nanobubbles (Bubble liposomes [BL]) that oscillate and collapse in an ultrasound field, generating heat and shock waves. We aimed to investigate the feasibility of cancer therapy using the combination of BL and ultrasound. In addition, we investigated the anti-tumor mechanism of this cancer therapy. Colon-26 cells were inoculated into the flank of BALB/c mice to induce tumors. After 8 days, BL or saline was intratumorally injected, followed by transdermal ultrasound exposure of tumor tissue (1 MHz, 0–4 W/cm[2], 2 min). The anti-tumor effects were evaluated by histology (necrosis) and tumor growth. In vivo cell depletion assays were performed to identify the immune cells responsible for anti-tumor effects. Tumor temperatures were significantly higher when treated with BL + ultrasound than ultrasound alone. Intratumoral BL caused extensive tissue necrosis at 3–4 W/cm[2] of ultrasound exposure. In addition, BL + ultrasound significantly suppressed tumor growth at 2–4 W/cm[2]. In vivo depletion of CD8[+] T cells (not NK or CD4[+] T cells) completely blocked the effect of BL + ultrasound on tumor growth. These data suggest that CD8[+] T cells play a critical role in tumor growth suppression. Finally, we concluded that BL + ultrasound, which can prime the anti-tumor cellular immune system, may be an effective hyperthermia strategy for cancer treatment.