Antibody-drug conjugates (ADCs) are among the most significant advances in clinical cancer treatments, however, they are haunted with fundamental issues like low drug/antibody ratio (DAR), need of large amount of antibody, and complex chemistry. Targeted nanomedicines while offering a promising alternative to ADCs are afflicted with drug leakage and inferior cancer-specificity. Herein, we developed an intelligent cell-selective nanotoxin based on anti-CD44 antibody-polymersome-DM1 conjugates (aCD44-AP-DM1) for potent treatment of solid tumors. DM1 was simultaneously coupled to vesicular membrane via disulfide bonds during self-assembly and anti-CD44 antibody was facilely clicked onto polymersome surface, tailor-making an optimal aCD44-AP-DM1 with a controlled antibody density of 5.0, extraordinary DAR of 275, zero drug leakage and rapid reduction-responsive DM1 release. aCD44-AP-DM1 displayed a high specificity and exceptional cytotoxicity toward MDA-MB-231 triple negative breast cancer, SMMC-7721 hepatocellular carcinoma and A549 non-small cell lung cancer cells with half-maximal inhibitory concentrations (IC50) of 21.4, 3.7 and 64.6 ng/mL, respectively, 3.6-47.2-fold exceeding non-targeted P-DM1. Intriguingly, the systemic administration of aCD44-AP-DM1 significantly suppressed subcutaneous MDA-MB-231 tumor xenografts in nude mice while intratumoral injection achieved complete tumor eradication in four out of five mice, without causing toxicity. This intelligent cell-selective nanotoxin has emerged as a better platform over ADCs for targeted cancer therapy.