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However, intra\u2010articular delivery of drugs to cartilage remains a challenge due to their rapid clearance within the joint. This problem is further exacerbated by the dense and negatively charged cartilage extracellular matrix (ECM). Cationic nanocarriers that form reversible electrostatic interactions with the anionic ECM can be an effective approach to overcome the electrostatic barrier presented by cartilage tissue. For an effective therapeutic outcome, the nanocarriers need to penetrate, accumulate, and be retained within the cartilage tissue. Nanocarriers that adhere quickly to cartilage tissue after intra\u2010articular administration, transport through cartilage, and remain within its full thickness are crucial to the therapeutic outcome. To this end, we used ring\u2010opening polymerization to synthesize branched poly(\n                    <jats:sc>l<\/jats:sc>\n                    \u2010lysine) (BPL) cationic nanocarriers with varying numbers of poly(lysine) branches, surface charge, and functional groups, while maintaining similar hydrodynamic diameters. Our results show that the multivalent BPL molecules, including those that are highly branched (i.e., generation two), can readily adhere and transport through the full thickness of cartilage, healthy and degenerated, with prolonged intra\u2010cartilage retention. Intra\u2010articular injection of the BPL molecules in mouse knee joint explants and rat knee joints showed their localization and retention. In summary, this study describes an approach to design nanocarriers with varying charge and abundant functional groups while maintaining similar hydrodynamic diameters to aid the delivery of macromolecules to negatively charged tissues.\n                  <\/jats:p>","DOI":"10.1002\/btm2.10612","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T02:35:48Z","timestamp":1697510148000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Branched poly\u2010\n                    <scp>l<\/scp>\n                    \u2010lysine for cartilage penetrating carriers"],"prefix":"10.1002","volume":"9","author":[{"given":"Gavin","family":"Gonzales","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering Duke University  Durham North Carolina 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