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<p>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.</p> Graphical Abstract <p></p>

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Hyaluronic acid-tailored prodrug nanoplatforms for efficiently overcoming colorectal cancer chemoresistance and recurrence by synergistic inhibition of cancer cell stemness

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月14日

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  • Xirui Duan,
  • Hailong Tian,
  • Peilan Peng,
  • Ping Zhou,
  • Ning Ding,
  • Guowen Liu,
  • Gary T. Bentley,
  • Canhua Huang,
  • Jun Yang,
  • Ke Xie

摘要

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.

Graphical Abstract