Hydrophobic photosensitizer zinc(II) phthalocyanine (ZnPc) was loaded into adamantane (Ad) modified nanochannels of mesoporous silica nanoparticles (MSNPs). The Ad units on the surface of MSNPs were complexed with amino-substituted β-cyclodextrin to enhance the solubility of the hybrid in aqueous solution. The amino groups on β-cyclodextrin also provide functional sites for further conjugation with targeting ligands toward targeted cancer therapy. Since the intercalation of the Ad spacer isolates loaded ZnPc and prevents its aggregation inside MSNPs, ZnPc exhibits its monomeric characteristics to effectively generate cytotoxic singlet oxygen ((1)O2) upon light irradiation (675 nm) in aqueous conditions, leading to efficient photodynamic activity for successful cancer treatment in vitro. Current research presents a convenient approach to maintain the monomeric state of hydrophobic photosensitizer ZnPc by rationally utilizing multifunctional MSNPs as the carriers. The novel hybrid with targeting capability achieves active photodynamic property of monomeric ZnPc in aqueous solution under light irradiation, which may find its way for practical photodynamic therapy in the future.