Phototherapy　for　non-invasive　cancer　treatment　has　been　extensively　studied.　An　urgent　challenge　in　phototherapy　application　is　to　fabricate　appropriate　targeted　agents　to　achieve　efficient　therapeutic　effect.　Herein,　a　molecular　and　supramolecular　approach　for　targeting　phototherapy　was　reasonably　designed　and　realized　through　the　axial　sulfonate　modification　of　silicon(IV)　phthalocyanines　(Pcs),　followed　by　supramolecular　interaction　with　albumin.　This　approach　can　not　only　improve　the　photoactivities　(e.g.,　fluorescence　emission　and　reactive　oxygen　species　production)　of　the　Pcs　but　also　enhance　their　tumor　targeting.　Most　importantly,　one　of　the　deigned　Pcs　(4)　can　target　HepG2　cells　through　dual　cell　pathways,　leading　to　an　extremely　high　phototoxicity　with　an　EC50(i.e.,　concentration　of　Pcs　to　kill　50%　of　cells　under　light　irradiation)　value　of　2.0　nM.　This　finding　presents　a　feasible　strategy　to　realize　efficient　targeting　phototherapy.　©　2022　American　Chemical　Society.　All　rights　reserved.