![]() ![]() Consequently, before RNA therapeutics can achieve their ultimate clinical potential to treat widespread human disease, the rate-limiting delivery problem of endosomal escape must be solved in a clinically acceptable manner. Here, we combine two technologies to achieve posttranscriptional gene silencing in tumor cells: Centyrins, alternative scaffold proteins binding plasma. Novel processing of biodegradable and biocompatible polymers at small scales for. However, similar to the cell membrane, endosomes comprise a lipid bilayer that entraps 99% or more of RNA therapeutics, even in semipermissive tissues such as the liver, central nervous system, and muscle. Centyrins, a novel protein scaffold with ideal properties for cancer. In spite of this clinical failure, the Adnectin-anti-VEGFR2 has become a model protein for development of technologies supporting. The overall design is reminiscent of a Lego construction, so we propose to call the scaffolds/nanobody ensemble Legobody. The size of the nanobody is increased to 120 kDa by two rigidly attached scaffolds. Unlike small-molecule therapeutics that are designed to passively diffuse across the cell membrane, macromolecular RNA therapeutics are too large, too charged, and/or too hydrophilic to passively diffuse across the cellular membrane and are instead taken up into cells by endocytosis. Here, we describe a versatile method that allows cryo-EM analysis of even the smallest protein once a tightly binding nanobody is available. However, before widespread use of RNA therapeutics becomes a reality, we must overcome a billion years of evolutionary defenses designed to keep invading RNAs from entering cells. RNA therapeutic activity is mechanistically driven by Watson–Crick base pairing to the target gene RNA without the requirement of prior knowledge of the protein structure, function, or cellular location. Recently, a design strategy to create small proteins called fluctuation-regulated affinity proteins (FLAPs) consisting of a structurally immobilized peptide from the complementarity-determining region (CDR) loops of mAbs (CDR-derived peptide) and a protein scaffold was developed. RNA therapeutics, including siRNAs, antisense oligonucleotides, and other oligonucleotides, have great potential to selectively treat a multitude of human diseases, from cancer to COVID to Parkinson's disease. ![]()
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