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The investigation of gene regulation therapeutics for the treatment of skin‐related diseases is rarely explored in part due to inefficient systemic delivery. In this study, a bottlebrush polymer‐antisense oligonucleotide (ASO) conjugate, termed pacDNA, designed to target IL‐17 receptor A (IL‐17RA), which is involved in psoriasis pathogenesis is presented. Systemic administration of pacDNA led to its accumulation in epidermis, dermis, and hypodermis of mouse skin, reduced IL‐17RA gene expression in skin, and significantly reversed the development of imiquimod (IMQ)‐induced psoriasis in a mouse model. These findings highlight the potential of the pacDNA as a promising nanoconstruct for systemic oligonucleotide delivery to the skin and for treating psoriasis and other skin‐related disorders through systemic administration.more » « lessFree, publicly-accessible full text available August 14, 2025
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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.more » « less
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null (Ed.)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.more » « less