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  1. null (Ed.)
  2. Abstract

    The development of new material platforms can improve our ability to study biological processes. Here, we developed a water‐compatible variant of a click‐like polymerization between alkynoates and secondary amines to form β‐aminoacrylate synthetic polyethylene glycol (PEG) based hydrogels. These materials are easy to access—PEG alkynoate was synthesized on a 100 gram scale and the amines were available commercially; these materials are also operationally simple to formulate—gel formation occurred upon simple mixing of precursor solutions without the need for initiators, catalysts, nor specialized equipment. Three‐dimensional cell culture experiments also indicated cytocompatibility of these gels with >90 % viability retained in THP‐1 and NIH/3T3 cells after 72 hours in culture. This hydrogel system therefore represents an alternative platform to other click and click‐like hydrogels with improved accessibility and user‐friendliness for biomaterials application.

     
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  3. Abstract

    The production of new proteins with messenger RNA (mRNA) has gained a broad interest due to its potential for addressing a wide range of diseases. Here, the design and characterization of novel ionizable poly(β‐amino ester)‐co‐poly(caprolactone) terpolymers, synthesized via the combination of the ring opening polymerization and the Michael step‐growth polymerization, are reported. The versatility of this method is demonstrated by varying the number of caprolactone units attached to each poly(β‐amino ester) (PBAE) terpolymer. The ability of the novel poly‐caprolactone (PCL)‐based PBAE materials to deliver mRNA is shown to depend on the physiochemical characteristics of the material, such as lipophilicity, as well as the formulation method used to complex the polymer with the oligonucleotide. This latter variable represents a previously unstudied aspect of PBAE library screens that can play an important role in identifying true top candidates for nucleic acid delivery. The most stable terpolymer is injected intravenously (IV) in mice and shows a transfection efficacy several times higher than the polyethylenimine (PEI) which is focused in the spleen, opening the possibility to use these biodegradable carriers in the intravenous delivery of antigen‐encoding mRNA for cancer immunotherapy and vaccination.

     
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  4. B lymphocytes regulate several aspects of immunity including antibody production, cytokine secretion, and T‐cell activation; moreover, B cell misregulation is implicated in autoimmune disorders and cancers such as multiple sclerosis and non‐Hodgkin's lymphomas. The delivery of messenger RNA (mRNA) into B cells can be used to modulate and study these biological functions by means of inducing functional protein expression in a dose‐dependent and time‐controlled manner. However, current in vivo mRNA delivery systems fail to transfect B lymphocytes and instead primarily target hepatocytes and dendritic cells. Here, the design, synthesis, and biological evaluation of a lipid nanoparticle (LNP) system that can encapsulate mRNA, navigate to the spleen, transfect B lymphocytes, and induce more than 60 pg of protein expression per million B cells within the spleen is described. Importantly, this LNP induces more than 85% of total protein production in the spleen, despite LNPs being observed transiently in the liver and other organs. These results demonstrate that LNP composition alone can be used to modulate the site of protein induction in vivo, highlighting the critical importance of designing and synthesizing new nanomaterials for nucleic acid delivery.

     
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