Platelet-armored nanoplatform to harmonize janus-faced IFN-γ against tumor recurrence and metastasis

Abstract

Interferon-γ (IFN-γ) plays contradictory roles in tumor immunology: (I) to activate positive host's immunity for eliminating tumor; (II) to induce negative adaptive immune resistance via up-regulating programmed death ligand-1 (PD-L1) expression for tumors to evade immune surveillance. The negative feedback loop between the IFN-γ recovery and the IFN-γ-induced PD-L1 up-regulation puts postoperative adjuvant chemotherapy into a dilemma. It is of great significance but challenging to manipulate the double-edge effects of IFN-γ against postoperative tumor progression. Herein, a platelet-engineered nanoplatform (PMF@DR NPs) capable of harmonizing janus-faced nature of IFN-γ was designed via uniquely co-assembling doxorubicin (Dox) and cyclin-dependent kinase 5 inhibitor roscovitine (Rosco) with platelet membrane fragment (PMF) as the particulate stabilizer. With PMF@DR NPs navigated by PMF to residual tumor, the Dox-activated immune response recovered IFN-γ secretion for positive host's immunity, while the IFN-γ-induced negative adaptive immune resistance was potently overcome by Rosco via disabling PD-L1 expression without dependence of IFN-γ stimulation. The negative feedback loop between IFN-γ recovery and PD-L1 up-regulation was thus potently disrupted in postoperative adjuvant chemotherapy. Our PMF@DR NPs not only harmonized janus-faced nature of IFN-γ to effectively regulate postoperative tumor progression, but also illustrated an innovative strategy for high-drug-loading biomimic nanoplatform.

Keywords: Adaptive immune resistance; IFN-γ; Nanoplatform; Platelet membrane; Postoperative adjuvant chemotherapy.