Abstract: We here report a non-gene therapy anti-tumor nanoparticles (I3C@cLANPs) based PTEN by loading indole-3-methanol (I3C) into the cross-linked lipoic acid nanoparticles (cLANPs) for triple-negative breast cancer (TNBC) treatment. I3C is a PTEN-specific natural activator while the poor PTEN-activation efficiency impedes its ability to achieve the PTEN-mediated tumor therapy. Due to the structural homology of lipoic acid (LA), the cLANPs hold not only LA-like anticancer activity but also PTEN-activation properties, which would synergistically potentiate the PTEN-activation efficiency. The in vitro and in vivo data showed that PTEN expression in the I3C@cLANPs group was 2.1 and 2.8 times higher than that of I3C, respectively. In antitumor evaluation based on the 4T1 tumor-bearing mice showed a tumor inhibitory rate (TIR) of 78.4% at the I3C usage of 20 mg kg^-1, 54.5% higher than that of I3C alone and 19.7% higher than that of first-line chemotherapy drug Doxorubicin hydrochloride (DOX). Thus, the I3C@cLANPs could address the low activation efficiency in the PTEN-mediated tumor strategy and avoid the risks of gene therapy, holding a good prospect for TNBC and related cancer treatment.

Key words: Triple-negative breast cancer, Indole-3-methanol, Lipoic acid, Synergistic therapy