A spreadable self-gelling hemostatic powder sensitizes CAR-NK cell therapy to prevent hepatocellular carcinoma recurrence postresection.

Adoptive natural killer cell therapy (ANKCT) harbors great potential for combating postsurgical hepatocellular carcinoma (HCC) recurrence, but its efficacy is limited by tumor microenvironment (TME)-meditated repression on NK cell function and insufficient NK cell homing to tumor sites. Therefore, herein we develop a nanocomposite sprayable self-gelling powder enabling liver-localized codelivery of three FDA-approved drugs including calcitriol (Cal), gemcitabine (Gem), and tazemetostat (Taz) to address these challenges. This powder can be laparoscopically spread to liver wound sites, where it rapidly absorbs interfacial liquid to form a bulk adhesive pressure-resistant hydrogel in situ, implying its application potential in minimally surgery. Moreover, its application to liver resection bed significantly sensitizes allogenic NK and EpCAM chimeric antigen receptor modified-NK-92 (EpCAM-CAR-NK) cell infusion to prevent HCC recurrence in orthotopic Heap1-6 tumor-bearing and patient-derived tumor xenograft (PDX) HCC murine models. Additionally, this powder can allow for an effective hemostatic effect in rat and porcine models due to its powerful tissue adhesion-seal and erythrocyte-aggregating effects. Altogether, our newly developed hemostatic self-gelling powder can significantly sensitize ANKCT to combat HCC recurrence in a manner compatible with surgical treatment of HCC.