HDAC6 inhibitor loaded bimetallene nanosheets with antagonizing thermoresistance for augmented mild photothermal therapy

Photothermal therapy (PTT) induces thermoresistance through cellular heat shock response, which impairs the therapeutic efficacy of the PTT. To resolve this problem, we developed a photothermal theranostics (denoted as PMH), which integrated the photothermal conversion agent of PdMo bimetallene with histone deacetylase 6 (HDAC6) selected inhibitor (ACY-1215), showing the synergistic antitumor effect both in vitro and in vivo. Mechanistically, under the photoacoustic imaging (PA) navigation, the released ACY-1215 triggered by NIR laser irradiation decrease the heat shock proteins (HSPs) expression and weaken the HDAC6-regulated HSP90 deacetylation, thus hindering the degradation of PTT-induced misfolded or unfold proteins through proteasome dependent pathway. Moreover, mild photothermal therapy (mPTT) treatment compromised the autophagy, which induced by HDAC6 inhibition, leading to mPTT-induced misfolded or unfold proteins further accumulation. Given that inhibition of HDAC6 plus mPTT contribute to tumor eradication. This study develops a promising combination strategy based on mPTT for future cancer treatment.