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In this work, the straightforward synthesis of amphiphilic zwitterionic bioderived block copolymers (BCPs) using glutamic acid (Glu) and cholesterol (Chol) as building blocks are reported. The previously established Glu‐derivative NBoc‐Glu‐OtBu‐methacrylate (NBoc‐Glu‐OtBu‐MA) serves as hydrophobic precursor for the zwitterionic block, while a mostly unexplored cholesteryl‐derived methacrylate monomer (Chol‐MA) with increased side chain flexibility functions as the hydrophobic block. In the first step, NBoc‐Glu‐OtBu‐MA is polymerized via reversible addition‐fragmentation chain‐transfer (RAFT) polymerization. Afterward, the linear polymer is chain‐extended with Chol‐MA, yielding P(NBoc‐Glu‐OtBu‐MA)n‐b‐(Chol‐MA)m BCPs with varying block ratios. After deprotection under acidic conditions, polymers with a block weight ratio of 87:13 (Glu‐OH‐MA:Chol‐MA) readily assemble into polymeric nanoparticles (NPs) of a desirable size below 100 nm diameter, making them good candidates for biomedical applications. The experimental results are supported using computations of the partition coefficients and machine learning models for the prediction of the polymer densities of the different BCPs. In addition, high (up to 20 wt.%) loading of the hydrophobic anti‐cancer drug 6‐mercaptopurine (6‐MP) is achieved in these NPs during the assembly process. The cytostatic activity of 6‐MP NPs is demonstrated in vitro on MDA‐MB‐231 breast cancer cells. These results emphasize the potential of amphiphilic zwitterionic bioderived NPs for the delivery of hydrophobic drugs. [ABSTRACT FROM AUTHOR]