Drug-carrier compatibility impacts drug delivery efficiency and resulting therapeutic efficacy and tolerability. Although numerous biodegradable carrier materials have been pursued over the past decades, chemical strategies that are sought to tailor therapeutic structures and their carriers together in a concerted effort remain rare yet may be powerful. Based on the principle of improving the structural similarity between these central components, we developed an omega-3 fatty acid-conjugated poly(ethylene glycol) (PEG) nanocarrier host that is capable of supramolecular assembly of a cytotoxic prodrug guest. To demonstrate the proof of concept, we ligated two docosahexaenoic acid (DHA) molecules and one PEG chain via a d-lysine linkage to produce an amphiphilic matrix DHA-PEG, which is suited for the encapsulation of active compounds, including a DHA monoconjugated camptothecin prodrug. The resulting DHA-PEG-cloaked nanoassemblies show superior stability and rapid cellular uptake compared with those formulated in clinically approved materials. In a chemically induced mouse model of colitis-associated colorectal cancer, administration of the camptothecin nanoassemblies demonstrated notable inhibition of colon tumor growth. Furthermore, this new delivery platform has low systemic toxicity and immunotoxicity in animals and is appealing for further investigation and clinical translation. Thus, through rational engineering of the carrier biomaterials and drug derivatization, the in vivo performance of drug delivery systems can be improved. This approach also establishes a methodology for leveraging synthetic chemistry tools to optimize delivery systems for a broad range of drug classes.