Hepatoma Metastasis-Inhibiting Supramolecular Nanoglycocalyx for Enhanced Type I Photodynamic Therapy.

Abstract

Type I photodynamic therapy (PDT) is well demonstrated to have low oxygen dependency. However, fully suppressing the risk of hypoxia-induced tumor metastasis during PDT remains a great challenge. In this study, a tetra-lactosylated amphiphilic Aza-BODIPY glycocluster (TLBP) is reported that self-assembles into a supramolecular nanoglycocalyx on hepatoma cell membranes, serving as an artificial extracellular matrix (ECM) to inhibit hepatoma metastasis while facilitating efficient Type I PDT. Molecular engineering demonstrates that multi-glycosylation promotes the transition of nanostructures from disordered to ordered self-assembly by regulating intermolecular interactions. This modification enables the TLBP glycocalyx to exhibit significant intermolecular electron transfer, generating superoxide anion radicals (O₂ ^-•) for Type I PDT. Moreover, the TLBP glycocalyx inhibits the PI3K-Akt signaling pathway by reducing Na⁺/K⁺-ATPase activity, leading to decreased migration and invasion of HepG2 cells. The synergistic antitumor effect of TLBP glycocalyx is further verified in a HepG2-bearing mouse model. This work innovatively utilizes glycosylation to regulate microelectronic properties and macroscopic nanoscale self-assembly characteristics, providing a novel concept for developing efficient synergistic anti-hepatoma strategies.