Efficient intratumoral penetration is essential for nanomedicine to eradicate pancreatic tumors. Although nanomedicine can enter the perivascular space of pancreatic tumors, their access to distal tumor cells, aloof from the vessels, remains a formidable challenge. Here, we synthesized an acid-activatable macromolecular prodrug of floxuridine (FUDR) - poly(FUDR-ketal), engineered a micellar nanomedicine of FUDR, and intravenously coadministered the nanomedicine with the tumor -penetrating peptide iRGD for enhanced treatment of pancreatic tumor. A FUDR-derived mono-isopropenyl ether was synthesized and underwent self -addition polymerization to afford the hydrophobic poly(FUDR-ketal), which was subsequently co -assembled with amphiphilic DSPEmPEG into the micellar nanomedicine with size of 12 nm and drug content of 56.8 wt% using nanoprecipitation technique. The acetone -based ketal-linked poly(FUDR-ketal) was triggered by acid to release FUDR to inhibit cell proliferation. In an orthotopic pancreatic tumor model derived from KPC ( Kras LSL-G12D/ + ; Trp53 LSL-R172H/ + ; Pdx1Cre ) cells that overexpress neuropilin-1 (NRP-1) receptor, iRGD improved penetration of FUDR nanomedicine into tumor parenchyma and potentiated the therapeutic efficacy. Our nanoplatform, along with iRGD, thus appears to be promising for efficient penetration and activation of acid -responsive nanomedicines for enhanced pancreatic cancer therapy.