Block linear copolymers comprising polycationic homopolymers and nonionic hydrophilic blocks compact nucleic acids into polyplex micelles. PEG, hydrophilic acrylamide, acrylate, and methacrylate polymers can arrange the nucleic acid in a micelle core and create a hydrophilic protective shell. For example, the PEG-b-PLL diblock copolymer assembles into monodisperse micelles with ASOs. Branched polycations include a type that has randomly distributed secondary chains branching from the primary polymer backbone. There are also dendrimers-polymers with fractal branching from a core. Nucleic acid carriers include branched PEI, branched PBAEs, as well as PLL, PAMAM, and poly(propyleneimine) (PPI) dendrimers (Figure ). Branched PEI, one of the most widely studied polycationic nucleic acid carriers, comprises primary, secondary, and tertiary amines, with different pKa values. Branched PEI provides efficient nucleic acid binding and extensive buffering capacity, which likely contribute to its outstanding performance. 302 PAMAM dendrimers, the most widely used dendrimer for nucleic acid delivery, comprise a hydrogen-bonding amide and tertiary amine groups in their cores and primary amine end groups in their coronas. Structural modifications have been attempted to lessen potential toxicity, enhance circulation time, and/or enhance targeting. Natural polymers including proteins and polysaccharides, particularly cationic collagen derivatives and chitosan, have been studied as nucleic acid delivery vehicles. Chitosan, a linear cationic polysaccharide, has been formulated into polyplexes to deliver miRNA to osteopathic tumors, for multiple myeloma, and for bone regeneration. An advantage of chitosan is that nucleic acids easily dissociate from the polymer upon cellular internalization. 311 Cationic collagen derivatives have been used for nucleic acid delivery to articular cartilage, for bone regeneration, and for treating tumor metastases. Cyclodextrins (CDs) are natural carbohydrate polymers for the delivery of therapeutic nucleic acids 315 that have shown clinical success. CDs are biocompatible cyclic oligosaccharides with a hydrophilic exterior surface and a hydrophobic interior cavity. Cationic CD derivatives assemble with siRNA via electrostatic interactions into stable gene delivery nanostructures of Similar to cationic lipid nanoparticles, polymeric nucleic acid carriers bind non-specifically to the negatively charged cell membrane via electrostatic interactions 318 and are internalized by endocytosis. Following endocytosis into early endosomes, polyplexes move through the progressively more acidic endosomes (pH 6.0-4.8). Escaping endosomal confinement is critical for nucleic acid delivery; therefore, scientists are developing and modifying polymer-based systems to promote endosomal escape. Peptides Peptides are structurally and functionally versatile, biocompatible, and can target cells; thus, they are attractive RNA carriers. Peptides that penetrate the cellular membrane and transfer to the cytoplasm, CPPs, are used most frequently for RNA delivery (Table ). CPPs have variable sequences, lengths, and polarities, and they can enter cells via multiple pathways, such as by forming a hole in the membrane or by endocytosis. CPPs deliver nucleic acids into cells via chemical conjugation or noncovalent complex formation with nucleic acids. Electrostatic and hydrophobic interactions between CPPs and nucleic acids result in self-assembly into peptide-based nanoparticles. Amphipathic CPPs have been developed using hydrophilic and hydrophobic domains to provide both nucleic acid complexation and membrane interactions. CPPs are promising, non-viral alternatives to lipid-or polymer-based carriers of therapeutic nucleic acids. The Tat peptide originated from the Tat protein of the human immunodeficiency virus (HIV). The positively charged oligoarginine peptides promote internalization by forming hydrogen bonds with the membrane sulfates and the nucleic acid phosphate groups. The histidine-rich peptide is efficient in siRNA delivery. The skin permeating and cell entering (SPACE) peptides facilitate the penetration of conjugated cargoes into the epidermis and dermis. Recently, fusion peptides were developed comprising SPACE and cationic oligoarginine linked by a GCG sequence. Nanocomplexes of fusion peptides and siRNA exhibited enhanced cellular uptake, gene silencing, and retention, possibly due to the synergistic effect of the oligoarginine and SPACE peptides. Oligoarginine electrostatically attracts siRNAs to form nanocomplexes, and the SPACE peptide interacts with the cellular membrane via hydrogen bonding.