Carnosic acid-induced co-self-assembly of metal-peptide complexes into a nanocluster-based framework with tumor-specific accumulation for augmented immunotherapy

Tumor immunotherapy by PD-1/PD-L1 blockade (PPB) has emerged as a standard of care treatment and can bring long-lasting clinical benefits, yet less than one-third of patients respond to it. While combination PPB therapies have shown improved outcomes, more optimal multimodality therapies, particularly those combinations with molecularly targeted therapies, are still required to improve the therapeutic benefit of PPB. Herein, we describe a design of PPB sensitizer with supramolecular nanostructure constructed through a dynamic combinatorial chemistry (DCC)-based co-self-assembled strategy. Upon the stimulation of a β-catenin inhibitor termed carnosic acid (CA), two competing molecular blocks three-dimensionally and orderly co-self-assembled into a nanocluster-based framework (CA-NBF) under thermo-dynamic control. With properties of tumor-specific accumulation and glutathione-triggered release, CA-NBF potently suppressed the Wnt/β-catenin signaling cascade in vitro and in vivo, while keeping a favorable safety feature. Moreover, CA-NBF potently restored the intratumoral infiltration of cytotoxic T lymphocyte cells and consequently promoted tumor response to Anti-PD-L1 antibody in B16F10 melanoma model and Anti-PD1 antibody in MC38 model of colon cancer. Given these encouraging results, this work may provide a new option for promoting the response of PPB therapy, and the DCC-based co-self-assembled strategy may be a promising tool to develop a class of supramolecular nanomedicines for the molecular targeted therapy of diseases including cancer.