Although cyclodextrin-based renal-clearable nanocarriers have a high potential for clinical translation in targeted cancer therapy, their designs remain to be optimized for tumour retention. Here we report on the design of a tailored structure for renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery. Twenty cyclodextrin derivatives with different charged moieties and spacers are synthesized and screened for colloidal stability. The resulting five candidates are evaluated for biodistribution and an optimized structure is identified. The optimized cyclodextrin shows a high tumour accumulation and is used for delivery of doxorubicin and ulixertinib. Higher tumour accumulation and tumour penetration facilitates tumour elimination. The improved antitumour efficacy is demonstrated in heterotopic and orthotopic colorectal cancer models.