Even with its vast potential, small interfering RNA (siRNA) therapeutics are faced with many impediments including instability in biological fluids and moderate cellular internalization/endosomal escape activities. Numerous lipid- and polymer-based nanocarriers were developed to address these issues, with the challenge of keeping the balance between stable complexation and endosomal escape. A pragmatic answer might lie within natural RNA binders such as neomycin B (Neo), a potent aminoglycoside antibiotic that is well-known for binding to various RNAs motifs. Neo contains six amines which are mostly ionized at physiological pH to facilitate electrostatic interaction with the anionic phosphates of RNAs. The perplexing versatility seen in Neo-RNA binding can be credited to its conformational flexibility arising from glycosidic bonds, an important part of Neo structure. In addition, the amino groups of Neo possess a wide range of pKas (5.4 to 8.8), which supplement its ability to achieve this intricate balance between complexation and effectual endosomal escape of siRNA in the target cells. We report the development of a novel Neo-derived unit poly-ion complex (uPIC), formed by electrostatic interactions between a single siRNA strand and two defined charge-regulated binary polyethylene glycol (PEG)-block-polycation copolymer chains wherein Neo operates as a cationic siRNA captor. This Neo-siRNA uPIC has a small size (around 20 nm) and presents excellent RNA binding and complexation, effective endosomal escape, and sustained blood circulation, suggesting the massive scope of utilizing Neo as a capable component of future PIC-type siRNA and other therapeutic nucleic acid delivery platforms.