We designed and synthesized three new berberine-based compounds, namely, pyridine-2,6-dimethyl-/2,2'-bipyridine-3,3'-dimethyl-tethered berberine dimers BD1 and BD2, and a tetrakis(4-benzyl)ethylene linked berberine tetramer BD4. We identified that the dimer BD2 and tetramer BD4, as well as 1,10-phenanthroline-2,9-dimethyl-linked berberine dimer BD3 previously reported by us, showed remarkable aggregation-induced emission (AIE) properties which endowed them with higher singlet oxygen ((1)O(2)) production ability than berberine. Of the four compounds, BD3 exhibits the lowest DeltaE(ST) energy with the highest (1)O(2) generation ability and thus was selected for further construction of AuNSs-BD3@HA (denoted as ABH, AuNSs = gold nanostars; HA = hyaluronic acid). The nanosystem of ABH shows a remarkable therapeutic effect toward breast cancer by combining photodynamic therapy (PDT) from BD3, photothermal therapy (PTT) from AuNSs, and the CD44-targeting capability of HA. The synergistically enhanced PDT and PTT induce superior cancer cell apoptosis/necrosis in vitro and anti-breast cancer activity in vivo. This study provides a new concept for PDT using natural product derivatives and their combination with PTT for efficient treatment of tumors.