Various　obstacles　[poor　tissue　penetration,　hypoxic　tumor　microenvironment,　and　reactive　oxygen　species　(ROS)　production　quenching　due　to　aggregation]　obstruct　imaging-guided　high-efficiency　phototherapy　targeting　tumors.　Herein,　nanophthalocyanine　(ZnPcN4-TF)　is　elaborately　designed　based　on　a　synthetic　phthalocyanine　derivative　(ZnPcN4)　and　nonimmunogenic　transferrin　(TF)　through　multiple　noncovalent　interactions　for　photoacoustic　(PA)　imaging-guided　phototherapy.　By　conjugating　electron-rich　amino　groups　effectively　suppressed　fluorescence　and　ROS　generation　due　to　the　strong　photoinduced　electron　transfer　effect,　ZnPcN4　became　an　ideal　photothermal　and　PA　imaging　agent.　ZnPcN4-TF　not　only　effectively　targeted　tumor　sites　and　accumulated　there,　but　also,　surprisingly,　facilitated　the　enhancement　of　ROS　production　via　a　type　I　process　in　an　aggregate　compared　to　ZnPcN4　itself,　potentially　due　to　accelerated　electron　transfer.　Simultaneously,　ZnPcN4-TF　had　a　substantially　more　powerful　photothermal　effect　than　ZnPcN4　itself.　Thus,　this　design　effectively　overcomes　the　obstacles　to　photodynamic　therapy　(aggregation-related　ROS　generation　quenching　in　a　hypoxic　environment).　Furthermore,　PA　imaging　solves　the　tissue　penetration　challenge　in　optical　imaging.　This　study　provides　a　broader　base　for　designing　novel　photosensitizers　to　improve　phototherapy　under　hypoxia.(Formula　presented)　©　2025　Chinese　Chemical　Society.　All　rights　reserved.