Biomimetic metal-phenolic network-coated elastin-like polypeptide micelles as an immunogenic cell death inducer for orthotopic glioma sonodynamic-chemodynamic-immune therapy

Abstract

Development of a theranostic nanomedicine to tackle orthotopic glioma remains to be challenging due to the difficulties of blood-brain barrier crossing and integration of different theranostic modalities. Herein, we report the design of biomimetic macrophage membrane (MM)-camouflaged metal-phenolic network (MPN)-coated micelles formed by amphiphilic elastin-like polypeptide (ELP)-chlorin e6 (Ce6) conjugates. We show that the MPN formed by assembly of Mn(II) and tannic acid (for short, TM) enables stable coating of the micelles, and the prepared Ce6-ELP@TM/MM exhibits good water dispersibility with a mean size of 67.8 nm. Under the tumor microenvironment condition, the Ce6-ELP@TM/MM could fast release Mn^2 + to generate reactive oxygen species (ROS) and facilitate Ce6 (a sonosensitizer) to generate singlet oxygen upon ultrasound irradiation, thereby killing cancer cells to induce immunogenic cell death (ICD) through chemodynamic/sonodynamic therapy. Moreover, the ROS-caused DNA damage could combine with Mn²⁺ to activate the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway of cancer cells, thus synergizing ICD to trigger enhanced antitumor immune responses to tackle an orthotopic mouse glioma model thanks to the MM-rendered BBB crossing and Mn²⁺-facilitated magnetic resonance imaging. The developed Ce6-ELP@TM/MM could be used as an ICD inducer to facilitate sonodynamic/chemodynamic/immune therapy of glioma or other tumor types.