Chemotherapy of lethal colorectal peritoneal metastases (PM) is notoriously challenged by poor drug delivery efficiency in PM tumors. Inspired by the histopathological examinations of PM tumors from colon cancer patients, a C[RGDfK] peptide-modified bioinspired lipoprotein (R-BLP) system was optimized from 8 formulations with profound penetrating ability in PM tumors of colorectal cancers. Then, a chemotherapeutic 7-ethyl-10-hydroxy-camptothecin (SN38)-loaded R-BLP (termed SR-BLP) was designed to promote their penetration in PM tumors and improve the chemotherapeutic efficacy. In CT26-induced PM models, SR-BLP exhibited better penetration profiles in PM tumors over a counterpart liposomal formulation. SR-BLP treatment produced an 80.03% suppression of PM incidence with obvious DNA damage and topoisomerase I (TOP I) downregulation and caused a 1.78-fold prolongation of survival time. Therefore, the histopathological features-inspired R-BLP provides an encouraging tumor-penetrating delivery platform for the effective chemotherapy of colorectal PM.