MMP‑2\nResponsive Gold Nanorods Loaded with\nHSP-70 siRNA for Enhanced Photothermal Tumor Therapy

Gold nanorods (Au NRs) are a valuable photothermal nanomaterial\nfor tumor therapy. However, when treated with Au NRs for photothermal\ntherapy, the expression of heat shock proteins in tumors will increase,\nwhich will induce heat resistance in tumor cells and reduce the photothermal\ntherapeutic effect of Au NRs. By RNA interference, the expression\nof heat shock proteins would be effectively inhibited to improve the\nefficasy of tumor photothermal therapy. However, deep and noninvasive\ntissue penetration remains a great obstacle to applying siRNA successfully.\nThus, the nanoplatform AGC/HSP-70 siRNA was designed for enhanced\nphotothermal tumor therapy by RNA interference. In the AGC/HSP-70\nsiRNA complex, the Au–S bond modified the matrix metalloproteinase-2\n(MMP-2)-sensitive peptide GPLGLAG on the surface of gold nanorods.\nMoreover, the natural basic polysaccharide (chitosan) was reacted\nwith the peptide by an amide bond for delivering heat shock protein\n70 silencing siRNA (HSP-70 siRNA). Modifying the MMP-2-sensitive linker\ncould cause more Au NRs to accumulate in tumors to exert a photothermal\neffect and promote the penetration of HSP-70 siRNA and chitosan complexes\ninto deep tumor tissues. <i>In vitro</i> experiments indicated\nthat the enzymolysis of the MMP-2-sensitive linker for AGC/HSP-70\nsiRNA could promote the cellular uptake and perinuclear distribution\nof HSP-70 siRNA in tumor cells, which may be due to the smaller size\nand positive electricity of the complexes. All of these results ensured\nthe efficient gene silencing effect of HSP-70 siRNA to enhance the\nphotothermal therapeutic effect of Au NRs in tumor tissues, as demonstrated\nby the gene silencing and cellular apoptotic experiments. <i>In vivo</i> experiments further proved that the AGC/HSP-70 siRNA\nnanoplatform efficiently improved the photothermal effect of Au NRs.\nIn summary, this work proved that AGC/HSP-70 siRNA is a promising\ndrug delivery strategy for enhancing the photothermal therapy of tumors\nby regulating the photothermal sensitivity of deep tumor cells as\nwell as retaining more Au NRs in tumor tissues, and also provides\na novel strategy for tumor photothermal therapy.