Although immunogenic cell death (ICD)-based chemoimmunotherapy elicits an immune response, it always focuses on eliminating “seeds” (tumor cells) but neglects “soil” (tumor microenvironment, TME), leading to tumor growth and metastasis. Herein, a type of detachable core–shell nanoplatform (DOX@HA-MMP-2-DEAP/CXB) is developed, which could swell in the acidic TME because of the protonation of the 3-diethylaminopropyl isothiocyanate (DEAP) inner core for celecoxib (CXB) release, while hyaluronic acid@doxorubicine (HA@DOX) prodrug in the outer shell could release by the cleavage of matrix metalloproteinase-2 (MMP-2) peptide. HA@DOX targets tumor cells precisely for triggering ICD. And CXB acts on multiple immune cells to remodulate TME, such as increasing the infiltration of dendritic cells (DCs) and T cells, decreasing the infiltration of the immunosuppressive cells, and eliminating the physical barriers between T cells and tumor cells. For comparison, HA-DOCA/DOX/CXB traditional nanoparticles are constructed. And DOX@HA-MMP-2-DEAP/CXB performs an impressive antitumor effect, which shows potential in enhancing the effect of chemoimmunotherapy.

中文翻译：

---

基于精确杀灭肿瘤种子和规范生长土壤策略的可分离纳米粒子增强化学免疫疗法。

尽管基于免疫原性细胞死亡 (ICD) 的化学免疫疗法会引发免疫反应，但它始终侧重于消除“种子”（肿瘤细胞）而忽略了“土壤”（肿瘤微环境，TME），从而导致肿瘤生长和转移。在此，开发了一种可分离的核壳纳米平台（DOX@HA-MMP-2-DEAP/CXB），由于塞来昔布的 3-二乙基氨基丙基异硫氰酸酯（DEAP）内核的质子化，它可以在酸性 TME 中膨胀（CXB）释放，而外壳中的透明质酸@阿霉素（HA@DOX）前药可以通过基质金属蛋白酶2（MMP-2）肽的切割而释放。HA@DOX 精确靶向肿瘤细胞以触发 ICD。并且 CXB 作用于多个免疫细胞以重新调节 TME，例如增加树突状细胞 (DC) 和 T 细胞的浸润，减少免疫抑制细胞的浸润，消除T细胞和肿瘤细胞之间的物理屏障。为了比较，构建了 HA-DOCA/DOX/CXB 传统纳米粒子。DOX@HA-MMP-2-DEAP/CXB 具有令人印象深刻的抗肿瘤作用，显示出增强化学免疫疗法效果的潜力。