Injectable adhesive hemostatic gel with tumor acidity neutralizer and neutrophil extracellular traps lyase for enhancing adoptive NK cell therapy prevents post-resection recurrence of hepatocellular carcinoma

Abstract

Post-resection recurrence remains an intractable problem in hepatocellular carcinoma (HCC) management. Natural killer (NK) cell infusion is considered as a promising cancer therapy, but acidic tumor microenvironment (TME) and neutrophil extracellular traps (NETs) greatly counteract its efficacy. Recently, polymer hydrogels have aroused much interest in tumor combination therapy, since they load and controllably release therapeutic agents with high bioavailability and low systemic toxicity. Therefore, a biocompatible hydrogel with tumor acidity neutralizer and NETs lyase may show promise for enhancing NK infusion to prevent post-resection HCC recurrence. Herein, a dual pH-responsive hydrogel with tumor acidity neutralizer (mesoporous bioactive glass nanoparticles) and NETs lyase (Deoxyribonuclease I, DNase I) is developed and used in combination with NK cell infusion for preventing post-resection HCC recurrence. The hydrogel can be injected to surgical margin and form an adhesive gel with a rapid hemostasis. Besides, it neutralizes tumor acidity to reduce tumor infiltration of immunosuppressive cells, and releases DNase I in a pH-responsive manner to degrade NETs. Moreover, this combination therapy significantly enhances NK cell infusion to combat post-surgical HCC recurrence without systemic toxicity. This study provides proof of concept that combination of NK cell adoptive therapy and hydrogel-based delivery system can successfully prevent post-resection HCC recurrence.

Keywords: Hepatocellular carcinoma; Injectable hydrogel; NK cell Adoptive therapy; Neutrophil extracellular traps; Tumor acidity.