A　pH-responsive　nanohybrid　(LDH-ZnPcPS4),　in　which　a　highly　hydrophilic　zinc(II)　phthalocyanine　tetra-α-substituted　with　4-sulfonatophenoxy　groups　(ZnPcPS4)　is　incorporated　with　a　cationic　layered　double　hydroxide　(LDH)　based　on　electrostatic　interaction,　has　been　specially　designed　and　prepared　through　a　facile　co-precipitation　approach.　ZnPcPS4　is　an　excellent　singlet-oxygen　generator　with　strong　absorption　at　the　near-infrared　region　(692　nm)　in　cellular　culture　media,　whereas　the　photoactivities　of　ZnPcPS4　were　remarkably　inhibited　after　incorporation　with　the　LDH.　The　nanohybrid　is　essentially　stable　in　aqueous　media　at　pH　7.4;　nevertheless,　in　slightly　acidic　media　of　pH　6.5　or　5.0,　ZnPcPS4　can　be　efficiently　released　from　the　LDH　matrix,　thus　leading　to　restoration　of　the　photoactivities.　The　nanohybrid　shows　a　high　photocytotoxicity　against　HepG2　cells　as　a　result　of　much　more　efficient　cellular　uptake　and　preferential　accumulation　in　lysosomes,　whereby　the　acidic　environment　leads　to　the　release　of　ZnPcPS4.　The　IC50　value　of　LDH-ZnPcPS4　is　as　low　as　0.053　μm,　which　is　24-fold　lower　than　that　of　ZnPcPS4.　This　work　provides　a　facile　approach　for　the　fabrication　of　photosensitizers　with　high　photocytotoxicity,　potential　tumor　selectivity,　and　rapid　clearance　character.　©　2015　Wiley-VCH　Verlag　GmbH　&　Co.　KGaA,　Weinheim.　drug　design　layered　compounds　nanoparticles　phthalocyanines　zinc.