Stimuli-responsive drug delivery systems based on polymeric nanovehicles are among the most promising treatment regimens for malignant cancers. Such intelligent systems that release payloads in response to the physiological characteristics of tumor sites have several advantages over conventional drug carriers, offering, in particular, enhanced therapeutic effects and decreased toxicity. The tumor microenvironment (TME) is acidic, suggesting the potential of pH-responsive nanovehicles for enhancing treatment specificity and efficacy. The synthetic polypeptide poly(l-histidine) (PLH) is an appropriate candidate for the preparation of pH-responsive nanovehicles because the pK_a of PLH (approximately 6.0) is close to the pH of the acidic TME. In addition, the pendent imidazole rings of PLH yield pH-dependent hydrophobic-to-hydrophilic phase transitions in the acidic TME, triggering the destabilization of nanovehicles and the subsequent release of encapsulated chemotherapeutic agents. Herein, we highlight the state-of-the-art design and construction of pH-responsive nanovehicles based on PLH and discuss the future challenges and perspectives of this fascinating biomaterial for targeted cancer treatment and “benchtop-to-clinic” translation.

基于聚合物纳米载体的刺激响应药物递送系统是最有希望的恶性肿瘤治疗方案之一。这种根据肿瘤部位的生理特征释放有效载荷的智能系统与传统药物载体相比具有几个优势，特别是提供了增强的治疗效果和降低的毒性。肿瘤微环境 (TME) 呈酸性，这表明 pH 响应纳米载体具有提高治疗特异性和疗效的潜力。合成多肽聚 ( l-组氨酸) (PLH) 是制备 pH 响应纳米载体的合适候选者，因为 p K _aPLH (约 6.0) 的 pH 值接近酸性 TME 的 pH 值。此外，PLH 的咪唑侧环在酸性 TME 中产生依赖于 pH 值的疏水到亲水相变，引发纳米载体的不稳定和随后释放封装的化学治疗剂。在这里，我们重点介绍了基于 PLH 的 pH 响应纳米载体的最新设计和构建，并讨论了这种引人入胜的生物材料在靶向癌症治疗和“台式到临床”转化中的未来挑战和前景。