The performances of second near‐infrared (NIR‐II) organic phototheranostic agents (OPTAs) depend on both molecular structure and molecular packing when used as nanoparticles (NPs). Herein, we proposed a facile structural isomerization‐induced 3D spatial donor (D)‐acceptor (A) interlocked network for achieving NIR‐II OPTAs. Two isomers, 4MNVDPP and 6MNVDPP were synthesized and formulated into NPs. 6MNVDPP, which has a larger electrostatic potential difference, exhibits a compact 3D spatial D‐A interlocked network in the crystal form, while 4MNVDPP forms 2D D‐D type J‐aggregates. Thus, 6MNVDPP NPs show red‐shifted NIR absorption and larger molar extinction coefficient than 4MNVDPP NPs. Thanks to the typical NIR‐II emission, superior photothermal‐stability, high photothermal conversion efficiency (89 %) and reactive oxygen species production capacity, 6MNVDPP NPs exhibit outstanding NIR‐II tiny capillary vasculature/tumor imaging ability and synergistic photothermal/photodynamic anti‐cancer effect in vivo.