Clustered　regularly　interspaced　short　palindromic　repeat　(CRISPR)-associated　Cas9　nuclease　system　(CRISPR/Cas9)　has　become　a　powerful　toolbox　as　a　gene　fixed-point　knock-out　method　and　hold　the　promising　prospect　for　cancer　therapy.　However,　the　biological　safety　of　the　viral　vectors　and　the　instability　of　exogenous　plasmid　in　blood　circulation　limits　its　application.　Herein,　we　reported　a　lactobionic　acid　functionalized　and　stimuli-responsive　chitosan　based　nanocomplex　to　co-deliver　sgVEGFR2/Cas9　plasmid　and　paclitaxel　for　hepatoma　carcinoma　therapy.　The　genome　editing　efficiency　of　sgVEGFR2/Cas9　in　the　nanosystem　achieved　up　to　38.6%　of　HepG2　cells　in　vitro　and　33.4%　of　tumor　tissues　in　vivo.　The　nanocomplex　suppressed　＞60%　VEGFR2　protein　expression　of　HepG2　cells　and　inhibited　hepatoma　carcinoma　(HCC)　tumor　progress　by　70%　on　mice.　In　vivo　study　indicated　the　obvious　tumor　accumulation　and　the　good　biosafety　of　the　nanosystem.　Moreover,　the　gene-drug　co-loaded　nanoparticles　stimulate　anti-tumorigenic　pathway　of　HCC　by　suppressing　pro-inflammatory　cytokines　(IL-6/IL-8)　and　tumor　angiogenesis-related　protein　(NF-κB　p65)　expression,　which　revealed　the　potential　pathway　inhibition　of　PTX　when　combined　with　the　gene　therapy　for　overexpression　VEGFR2　on　HCC　cells.　Overall,　this　strategy　provided　a　versatile　method　for　high　efficiency　CRISPR/Cas9　system　delivery　and　showed　tremendous　application　prospect　for　gene-chemo　synergistic　therapy.　©　2020　Elsevier　B.V.