The global burden of colorectal cancer (CRC), the third most commonly diagnosed malignancy, continues to rise. Therefore, more effective and less toxic therapies are needed for CRC. CPT-11 (also called irinotecan), the standard-of-care treatment for CRC, has only had limited effects on survival outcomes. In vivo, CPT-11 must be converted to an active metabolite, SN38, to exert antitumor activity in the presence of carboxylesterases, but the conversion rate is extremely low (usually less than 8%). To fully harness the active SN38 compound, we showed here that esterification of SN38 using α-linolenic acid (LNA) generated a prodrug (termed LSN38), which can be formulated in pharmaceutically acceptable surfactants, such as polysorbate 80. Upon blending with an aqueous ethanolic solution, the mixture of LSN38/polysorbate 80 formed self-emulsifying nanomicelles (termed LSN38 NMs), enabling systemic injection. Unlike the insufficient release of active SN38 from CPT-11, drug activation from the LSN38 prodrug was quantitative and relied on esterase, which is abundant in cancerous cells. Pharmacokinetics studies revealed that polysorbate 80-based nanomicelles stably constrained the prodrug in the reservoir and prolonged blood circulation compared to CPT-11. Furthermore, LSN38 NMs showed superior therapeutic efficacy against a colorectal xenograft-bearing mouse model that failed to be treated with clinically approved CPT-11. Overall, these studies highlight the feasibility of converting a chemotherapeutic agent that is not miscible or compatible with pharmaceutical surfactants into an injectable self-emulsifying formulation. This approach could be applied to rescue other drugs or drug candidates that are abandoned in the preclinical stages due to pharmaceutical challenges.