Synthesis of multi-branched Au nanocomposites with distinct plasmon resonance in NIR-II window and controlled CRISPR-Cas9 delivery for synergistic gene-photothermal therapy

Clinical implementation of photothermal therapy (PTT) is mainly hampered by limited tissue penetration, undesirable thermal damage to normal tissues, and thermotolerence induced by heat shock proteins (HSPs). To overcome these obstacles, we constructed a novel gene-photothermal synergistic therapeutic nanoplatform composed of a multi-branched Au nanooctopus (AuNO) core and mesoporous polydopamine (mPDA) shell, followed by CRISPR-Cas9 ribonucleoprotein (RNP) loading and then polyethylene glycol-folic acid (PEG-FA) coating. AuNO was simply synthesized by adjusting the ratio of cetyltrimethylammonium chloride (CTAC) and cetyltrimethylammonium bromide (CTAB), which showed significant localized surface plasmon resonances in the NIR-II window, and exhibited an excellent tissue penetration capability and high photothermal conversion efficiency (PCE, 47.68%). Even, the PCE could be further increased to 66.17% by mPDA coating. Furthermore, the sequential modification of AuNO@mPDA using RNP and PEG-FA can down-regulate HSP90α expression at tumor sites, enhance apoptosis and reduce the heat resistance of cancer cells. The synergistic effect of enhanced photothermal capacity and reduced thermoresistance addressed the multiple limitations of PTT, and presented excellent in vitro and in vivo antitumor efficacy, having great potential for the clinical application of PTT.