Noncationic polymer-assisted carrier for nucleic acid drug delivery

Nucleic acid drugs are emerging as a novel biotherapeutic modality for disease treatment, targeting nucleic acids to regulate the protein translation process and thereby facilitating disease management. They hold significant promise in biomedical applications and treatment avenues. Given their negative charge, high molecular weight, and hydrophilic properties, nucleic acid drugs require carriers to traverse multiple biological barriers and facilitate intracellular delivery. Cationic material-based carriers present an unprecedented opportunity to address these challenges through electrostatic interactions with nucleic acids. However, concerns regarding the biosafety and cytotoxic responses of cationic materials have emerged in early clinical studies. As a result, the use of non-cationic polymer carriers, by controlling or circumventing the use of cationic materials, represents a promising approach for nucleic acid delivery. In this review, we highlight various designs of non-cationic polymer carriers that go beyond the principle of electrostatic interactions, including conjugation, chemical bonding, physical crosslinking, hydrophobic interactions, and coordination bonding with nucleic acids. Additionally, we discuss strategies for enhancing the efficiency of nucleic acid delivery and therapeutic effects of non-cationic polymer carriers, focusing on targeted delivery, cellular internalization, and endosomal escape.