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We have developed a non-cationic transfection vector in the form of bottlebrush polymer-antisense oligonucleotide (ASO) conjugates. Termed pacDNA (polymer-assisted compaction of DNA), these agents show improved biopharmaceutical characteristics and antisense potency in vivo while suppressing non-antisense side effects. Nonetheless, there still is a lack of the mechanistic understanding of the cellular uptake, subcellular trafficking, and gene knockdown with pacDNA. Here, we show that the pacDNA enters human non-small cell lung cancer cells (NCI-H358) predominantly by scavenger receptor-mediated endocytosis and macropinocytosis and trafficks via the endolysosomal pathway within the cell. The pacDNA significantly reduces a target gene expression (KRAS) in the protein level but not in the mRNA level, despite that the transfection of certain free ASOs causes ribonuclease H1 (RNase H)-dependent degradation of KRAS mRNA. In addition, the antisense activity of pacDNA is independent of ASO chemical modification, suggesting that the pacDNA always functions as a steric blocker. 

The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRAS MUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)–conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA–protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non–small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush–ASO conjugate is a promising therapeutic platform for the treatment of KRAS -driven human cancers and warrant further preclinical and clinical development. 

Deep integration of nucleic acids with other classes of materials has become the basis of many useful technologies. Among these biohybrids, nucleic acid-containing copolymers have seen rapid development in both chemistry and applications. This review focuses on the various synthetic approaches for accessing nucleic acid–polymer biohybrids spanning post-polymerization conjugation, nucleic acids in polymerization, solid-phase synthesis, and nucleoside/nucleobase-functionalized polymers. We highlight the challenges associated with working with nucleic acids with each approach and the ingenuity of the solutions, with the hope of lowering the entry barrier and inspiring further investigations in this exciting area. 

Self-immolative polymers (SIPs) have been under development for over a decade, and efforts for their application followed shortly after their inception. One main area of application of SIPs is biomedicine, where they are used to construct devices and biosensors, develop new biotechnology abilities, or directly interface with the living system. Where traditional polymers are stable at room temperature, SIPs undergo rapid degradation when a labile capping group is removed, allowing SIPs to offer a highly unusual degradation profile compared with traditional polymers. This review summarizes the recent efforts to leverage the unique properties of SIPs for biomedical purposes, which are categorized into sensors, drug delivery, and biotechnology. By doing so, this review aims to stimulate future studies in this rapidly growing and promising area.