Nucleic acid therapeutics are used for silencing, expressing or editing genes in vivo. However, their systemic stability and targeted delivery to bone marrow resident cells remains a challenge. In this study we present a nanotechnology platform based on natural lipoproteins, designed for delivering small interfering RNA (siRNA), antisense oligonucleotides and messenger RNA to myeloid cells and haematopoietic stem and progenitor cells in the bone marrow. We developed a prototype apolipoprotein nanoparticle (aNP) that stably incorporates siRNA into its core. We then created a comprehensive library of aNP formulations and extensively characterized their physicochemical properties and in vitro performance. From this library, we selected eight representative aNP-siRNA formulations and evaluated their ability to silence lysosomal-associated membrane protein 1 (Lamp1) expression in immune cell subsets in mice after intravenous administration. Using the most effective aNP identified from the screening process, we tested the platform’s potential for therapeutic gene silencing in a syngeneic murine tumour model. We also demonstrated the aNP platform’s suitability for splice-switching with antisense oligonucleotides and for protein production with messenger RNA by myeloid progenitor cells in the bone marrow. Our data indicate that the aNP platform holds translational potential for delivering various types of nucleic acid therapeutics to myeloid cells and their progenitors.

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Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.

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The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, nucleic acid therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing. Their clinical translation, however, depends on delivery technologies that improve stability, facilitate internalization and increase target affinity. Here, we review four platform technologies that have enabled the clinical translation of nucleic acid therapeutics: antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles and adeno-associated virus vectors. For each platform, we discuss the current state-of-the-art clinical approaches, explain the rationale behind its development, highlight technological aspects that facilitated clinical translation and provide an example of a clinically relevant genetic drug. In addition, we discuss how these technologies enable the development of cutting-edge genetic drugs, such as tissue-specific nucleic acid bioconjugates, messenger RNA and gene-editing therapeutics.

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In the slipstream of targeting the adaptive immune system, innate immunotherapy strategies are being developed. In this context, technologies based on natural carrier vehicles that inherently interact with the innate immune system, are increasingly being considered. Immunoregulatory nanotherapeutics based on natural apolipoprotein A1 (apoA1) are discussed here. This protein is a helical, amphipathic macromolecule and the main constituent of high-density lipoprotein. In that capacity, apoA1 interacts specifically with innate immune cells, such as monocytes and macrophages, to collect and transport lipophilicmolecules throughout the body. Exactly these unique features make apoA1 a compelling elementary constituent of biocompatible self-assembled nanotherapeutics. Such apoA1-based nanotherapeutics (A1-nanotherapeutics) can be engineered and functionalized to induce or mitigate an innate immune response or to orchestrate an adaptive immune response through antigen delivery to dendritic cells. The authors first discuss apoA1’s properties and how these can be exploited to generate libraries of A1-nanotherapeutics using advanced manufacturing approaches such as microfluidics or continuous flow methods. Using high-throughput in vitro screening methods and in vivo imaging to identify promising formulations are then recommend. Finally, Three distinct immunotherapy strategies are proposed to effectively treat a variety of diseases— including cancer, infection, and cardiovascular disease—and promote allograft survival in transplantation.

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Nanomedicines are extensively employed in cancer therapy. We here propose four strategic directions to improve nanomedicine translation and exploitation. (1) Patient stratification has become common practice in oncology drug development. Accordingly, probes and protocols for patient stratification are urgently needed in cancer nanomedicine, to identify individuals suitable for inclusion in clinical trials. (2) Rational drug selection is crucial for clinical and commercial success. Opportunistic choices based on drug availability should be replaced by investments in modular (pro)drug and nanocarrier design. (3) Combination therapies are the mainstay of clinical cancer care. Nanomedicines synergize with pharmacological and physical co-treatments, and should be increasingly integrated in multimodal combination therapy regimens. (4) Immunotherapy is revolutionizing the treatment of cancer. Nanomedicines can modulate the behaviour of myeloid and lymphoid cells, thereby empowering anticancer immunity and immunotherapy efficacy. Alone and especially together, these four directions will fuel and foster the development of successful cancer nanomedicine therapies.

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