Peptide nanocarriers co-delivering an antisense oligonucleotide and photosensitizer elicit synergistic cytotoxicity

Combination therapies demand co-delivery platforms with efficient entrapment of distinct payloads and specific delivery to cells and possibly organelles. Herein, we introduce the combination of two therapeutic modalities, gene and photodynamic therapy, in a purely peptidic platform. The simultaneous formation and cargo loading of the multi-micellar platform is governed by self-assembly at the nanoscale. The multi-micellar architecture of the nanocarrier and the positive charge of its constituent micelles offer controlled dual loading capacity with distinct locations for a hydrophobic photosensitizer (PS) and negatively charged antisense oligonucleotides (ASOs). Moreover, the nuclear localization signal (NLS) sequence built-in the peptide targets PS + ASO-loaded nanocarriers to the nucleus. Breast cancer cells treated with nanocarriers demonstrated photo-triggered enhancement of radical oxygen species (ROS) associated with increased cell death. Besides, delivery of ASO payloads resulted in up to 90 % knockdown of Bcl-2, an inhibitor of apoptosis that is overexpressed in more than half of all human cancers. Simultaneous delivery of PS and ASO elicited synergistic apoptosis to an extent that could not be reached by singly loaded nanocarriers or the free form of the drugs. Both, the distinct location of loaded compounds that prevents them from interfering with each other, and the highly efficient cellular delivery support the great potential of this versatile peptide platform in combination therapy.