微卫星不稳定性高（MSI-H）结直肠癌（CRC）对免疫检查点抑制剂（ICI）的治疗反应确实令人惊讶；然而，获得性耐药的出现对这些患者的生存构成了更大的威胁。在此，MSI-H CRC 样本的生物信息学分析表明，Wnt 信号通路代表了获得性免疫再激活的一个有希望的靶点，而随后的分析和生化测试证实了 Wnt 过度活跃的 CRC 细胞与人血清白蛋白 (HSA) 参与巨胞饮作用的倾向。这些发现启发我们开发一种工程化 HSA，它不仅具有特异性靶向癌细胞的能力，而且还能有效抑制这些恶性细胞内的 Wnt/β-连环蛋白级联。为了实现这一目标，对已报道的Wnt小分子抑制剂进行了全面筛选，以评估其与HSA的亲和力，发现鼠尾草酸（CA）表现出最高的亲和力，同时揭示了多个结合位点。进一步的研究表明，CA HSA 能够将 HSA 工程化为球形且尺寸可调的纳米结构，称为 eHSA（工程 HSA 颗粒），这证明了优化的巨胞饮依赖性细胞内化。正如预期的那样，eHSA 有效抑制了 Wnt 信号通路并重新激活了体内获得性免疫反应。此外，eHSA 成功恢复了 MSI-H CRC 皮下和原位小鼠同种移植模型以及 MSI-H CRC 人源化 hu-PBMC 患者来源原位异种移植 (PDOX) 小鼠模型对抗 PD1 抗癌作用的敏感性。同时保持良好的安全状况。这种临床上可行的免疫再激活策略的集体实施不仅能够为结直肠癌治疗提供Wnt抑制剂，而且还可以作为精准医学引导的纳米药物开发的典范，有效利用病理状态下的特定细胞适应症。

The therapeutic response of microsatellite instability-high (MSI-H) colorectal cancer (CRC) to immune checkpoint inhibitors (ICI) is indeed surprising; however, the emergence of acquired resistance poses an even greater threat to the survival of these patients. Herein, bioinformatics analysis of MSI-H CRC samples revealed that Wnt signaling pathway represents a promising target for acquired immune reactivation, while subsequent analysis and biochemical testing substantiated the inclination of Wnt-hyperactive CRC cells to engage in macropinocytosis with human serum albumin (HSA). These findings have inspired us to develop an engineered HSA that not only possesses the ability to specifically target cancer cells but also effectively suppresses the Wnt/β-catenin cascade within these malignant cells. In pursuit of this objective, a comprehensive screening of reported Wnt small-molecule inhibitors was conducted to evaluate their affinity with HSA, and it was discovered that Carnosic acid (CA) exhibited the highest affinity while simultaneously revealing multiple binding sites. Further investigation revealed that CA HSA the capability to engineer HSA into spherical and size-tunable nanostructures known as eHSA (Engineering HSA particle), which demonstrated optimized macropinocytosis-dependent cellular internalization. As anticipated, eHSA effectively suppressed the Wnt signaling pathway and reactivated the acquired immune response in vivo. Furthermore, eHSA successfully restored sensitivity to Anti-PD1's anticancer effects in both subcutaneous and orthotopic mouse homograft models of MSI-H CRC, as well as a humanized hu-PBMC patient-derived orthotopic xenograft (PDOX) mouse model of MSI-H CRC, all while maintaining a favorable safety profile. The collective implementation of this clinically viable immune reactivation strategy not only enables the delivery of Wnt inhibitors for CRC therapy, but also serves as an exemplary demonstration of precision-medicine-guided nanopharmaceutical development that effectively harnesses specific cellular indications in pathological states.