Abstract

Oligonucleotide therapeutics hold transformative potential, yet their clinical translation is hindered by delivery barriers, including rapid renal/hepatic clearance and poor organ specificity. Bottlebrush polymers conjugates have emerged as a promising vector to address these limitations, but conventional architectures with uniform backbones can only achieve an unmodifiable, rigid biodistribution profile. Here, we report a library of sequence-defined digital bottlebrush polymers, precisely engineered with controlled placements of chemical motifs that modify physiochemical properties - including lipids, cholesterol, and cationic groups - along a polyphosphodiester backbone. Systematic evaluation of the digital bottlebrush polymer library reveals distinct structure-property relationships and enables organ-biased systemic delivery to several traditionally difficult-to-reach tissues, including muscle and skin. In a mouse model of rheumatoid arthritis, a single dose of a spleen-homing polymer-conjugated antisense oligonucleotide targeting TNF-α achieves potent knockdown and drives full functional recovery. These findings establish a versatile design framework for tailoring bottlebrush polymers to specific therapeutic applications. ### Competing Interest Statement The authors have declared no competing interest. National Science Foundation Ice Core Facility, https://ror.org/05sk14837, 2004947 National Institute of General Medical Sciences, 1R01GM121612 National Cancer Institute, 4R42CA275425, 5R01CA251730 Department of Defense Congressionally Directed Medical Research Programs, CDMRP MD230034