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Creators/Authors contains: "Shepherd, Sarah J."

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  1. Abstract Lipid nanoparticle-mediated RNA delivery holds great potential to treat various liver diseases. However, targeted delivery of RNA therapeutics to activated liver-resident fibroblasts for liver fibrosis treatment remains challenging. Here, we develop a combinatorial library of anisamide ligand-tethered lipidoids (AA-lipidoids) using a one-pot, two-step modular synthetic method and adopt a two-round screening strategy to identify AA-lipidoids with both high potency and selectivity to deliver RNA payloads to activated fibroblasts. The lead AA-lipidoid AA-T3A-C12 mediates greater RNA delivery and transfection of activated fibroblasts than its analog without anisamide and the FDA-approved MC3 ionizable lipid. In a preclinical model of liver fibrosis, AA-T3A-C12 enables ~65% silencing of heat shock protein 47, a therapeutic target primarily expressed by activated fibroblasts, which is 2-fold more potent than MC3, leading to significantly reduced collagen deposition and liver fibrosis. These results demonstrate the potential of AA-lipidoids for targeted RNA delivery to activated fibroblasts. Furthermore, these synthetic methods and screening strategies open a new avenue to develop and discover potent lipidoids with targeting properties, which can potentially enable RNA delivery to a range of cell and tissue types that are challenging to access using traditional lipid nanoparticle formulations. 
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  2. Nanoparticle (NP)-based therapeutics have ushered in a new era in translational medicine. However, despite the clinical success of NP technology, it is not well-understood how NPs fundamentally change in biological environments. When introduced into physiological fluids, NPs are coated by proteins, forming a protein corona (PC). The PC has the potential to endow NPs with a new identity and alter their bioactivity, stability, and destination. Additionally, the conformation of proteins is sensitive to their physical and chemical surroundings. Therefore, biological factors and protein–NP-interactions can induce changes in the conformation and orientation of proteins in vivo . Since the function of a protein is closely connected to its folded structure, slight differences in the surrounding environment as well as the surface characteristics of the NP materials may cause proteins to lose or gain a function. As a result, this can alter the downstream functionality of the NPs. This review introduces the main biological factors affecting the conformation of proteins associated with the PC. Then, four types of NPs with extensive utility in biomedical applications are described in greater detail, focusing on the conformation and orientation of adsorbed proteins. This is followed by a discussion on the instances in which the conformation of adsorbed proteins can be leveraged for therapeutic purposes, such as controlling protein conformation in assembled matrices in tissue, as well as controlling the PC conformation for modulating immune responses. The review concludes with a perspective on the remaining challenges and unexplored areas at the interface of PC and NP research. 
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  3. Multiple myeloma (MM), a hematologic malignancy that preferentially colonizes the bone marrow, remains incurable with a survival rate of 3 to 6 mo for those with advanced disease despite great efforts to develop effective therapies. Thus, there is an urgent clinical need for innovative and more effective MM therapeutics. Insights suggest that endothelial cells within the bone marrow microenvironment play a critical role. Specifically, cyclophilin A (CyPA), a homing factor secreted by bone marrow endothelial cells (BMECs), is critical to MM homing, progression, survival, and chemotherapeutic resistance. Thus, inhibition of CyPA provides a potential strategy to simultaneously inhibit MM progression and sensitize MM to chemotherapeutics, improving therapeutic response. However, inhibiting factors from the bone marrow endothelium remains challenging due to delivery barriers. Here, we utilize both RNA interference (RNAi) and lipid–polymer nanoparticles to engineer a potential MM therapy, which targets CyPA within blood vessels of the bone marrow. We used combinatorial chemistry and high-throughput in vivo screening methods to engineer a nanoparticle platform for small interfering RNA (siRNA) delivery to bone marrow endothelium. We demonstrate that our strategy inhibits CyPA in BMECs, preventing MM cell extravasation in vitro. Finally, we show that siRNA-based silencing of CyPA in a murine xenograft model of MM, either alone or in combination with the Food and Drug Administration (FDA)-approved MM therapeutic bortezomib, reduces tumor burden and extends survival. This nanoparticle platform may provide a broadly enabling technology to deliver nucleic acid therapeutics to other malignancies that home to bone marrow.

     
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