Ultrasound-responsive spherical nucleic acid against c-Myc/PD-L1 to enhance anti-tumoral macrophages in triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype because of its aggressive behavior and limited therapeutic targets. c-Myc is hyperactivated in the majority of TNBC tissues, however, it has been considered an "undruggable" target due to its disordered structure. Herein, we developed an ultrasound-responsive spherical nucleic acid (SNA) against c-Myc and PD-L1 in TNBC. It is a self-assembled and carrier-free system composed of a hydrophilic small-interfering RNA (siRNA) shell and a hydrophobic core made of a peptide nucleic acid (PNA)-based antisense oligonucleotide (ASO) and a sonosensitizer. We accomplished significant enrichment in the tumor by enhanced permeability and retention (EPR) effect, the controllable release of effective elements by ultrasound activation, and the combination of targeted therapy, immunotherapy and physiotherapy. Our study demonstrated significant anti-tumoral effects in vitro and in vivo. Mass cytometry showed an invigorated tumor microenvironment (TME) characterized by a significant alteration in the composition of tumor-associated macrophages (TAM) and decreased proportion of PD-1-positive (PD-1+) T effector cells after appropriate treatment of the ultrasound-responsive SNA (USNA). Further experiments verified that tumor-conditioned macrophages residing in the TME were transformed into the anti-tumoral population. Our finding offers a novel therapeutic strategy against the "undruggable" c-Myc, develops a new targeted therapy for c-Myc/PD-L1 and provides a treatment option for the TNBC.