A subset of residual colorectal cancer (CRC) cells with stemness features exhibits a transient adaptive resistance after chemotherapy, limiting durable therapeutic benefits and even accelerating tumor recurrence. To tackle this problem, we have developed a targeted polymer prodrug nanoplatform (CHH-T/NPs) capable of synergistically inhibiting cancer cell stemness by modulating intracellular metabolism and inhibiting protective autophagy. Hyaluronic acid (HA) acts as a tumor-targeting molecular backbone, α-cyanohydroxycinnamic acid (CHC) is an inhibitor of monocarboxylic acid transporter 1 (MCT1), and hydroxychloroquine sulfate (HCQ) is an inhibitor of autophagy. These compounds were loaded on the HA backbone to form a polymeric prodrug, CHH, with pH-responsive ester bonds. CHH was self-assembled with mitochondria-targeting IR820 (T820), resulting in the formation of CHH-T/NPs. CHC and T820 disrupted cellular metabolism by inducing mitochondrial dysfunction and inhibiting lactate transport, leading to a synergistic inhibition of cancer cell stemness. Simultaneously, HCQ effectively inhibited autophagy to disrupt the self-protection mechanism of CRC cells. As anticipated, CHH-T/NPs effectively suppressed the chemoresistance and postoperative recurrence of CRC in subcutaneous and in situ tumors models. Taken together, this approach presents a promising strategy for overcoming CRC chemoresistance and recurrence through the synergistic inhibition of cancer cell stemness.
