Nanoscale metal organic frameworks (NMOFs) with porous structure and inherent biodegradability are attractive nanomedicine platforms. In addition to conventional particulate NMOFs, two-dimensional (2D) NMOFs are emerging as a unique type of NMOFs which however have been relatively less explored for nanomedicine applications. Herein, 2D-NMOFs composed of Zn and tetrakis(4-carboxyphenyl) porphyrin (TCPP) are fabricated and functionalized with polyethylene glycol (PEG). Compared to their particulate counterpart, such 2D-NMOFs show greatly increased drug loading capacity and enhanced light-triggered singlet oxygen production, promising for chemotherapy and photodynamic therapy (PDT), respectively. Utilizing the porphyrin structure of TCPP, our 2D-NMOFs could be labeled with a diagnostic radioisotope, Tc, for single photon emission computer tomography (SPECT) imaging, which reveals efficient tumor homing of those 2D-NMOFs upon intravenous injection. While offering a remarkable synergistic in vivo antitumor effect for the combined chemo-PDT, such 2D-NMOFs show efficient biodegradation and rapid renal clearance. Our work presents the great promise of 2D-NMOFs for nanomedicine applications. [Figure not available: see fulltext.].