Photothermal　therapy　(PTT)　is　a　promising　strategy　for　cancer　treatment.　However,　the　development　of　highly　efficient　photothermal　agents　with　excellent　biosafety,　particularly　with　low　liver　retention,　is　very　meaningful　for　clinical　applications,　but　it　is　also　challenging.　We　herein　prepared　a　pH-sensitive　nanoagent　(NanoPc3)　by　the　self-assembly　of　a　zinc(ii)　phthalocyanine　substituted　with　hexadeca-sulphonates　linked　by　hydrazone　bonds　for　photoacoustic　imaging　and　PTT.　Due　to　the　highly　negative　surface　potential　(−30.80　mV　in　water),NanoPc3could　effectively　escape　the　phagocytosis　of　the　reticuloendothelial　system　and　be　rapidly　cleared　from　normal　tissues,　leading　to　little　accumulation　in　the　liver　and　excellent　biosafety.　The　highly　negatively-chargedNanoPc3changed　into　nearly　neutral　nanoparticles　(NanoPc3H)　under　slightly　acidic　conditions,　resulting　in　enhanced　cellular　uptake　and　retention　time　in　tumor　tissues.　Moreover,　the　tumor　of　H22　tumor-bearing　mice　treated　withNanoPc3almost　disappeared,　suggesting　an　outstanding　photothermal　antitumor　effect.NanoPc3also　hardly　showed　skin　phototoxicity　under　irradiation.　Its　excellent　antitumor　effect　and　biosafety　makeNanoPc3highly　promising　in　clinical　applications.　This　work　will　provide　a　new　strategy　for　the　design　of　tumor-targeted　photothermal　nanoagents　with　high　biosafety.　©　The　Royal　Society　of　Chemistry　2021.