Multivalency-assisted membrane-penetrating siRNA delivery sensitizes photothermal ablation via inhibition of tumor glycolysis metabolism.

The success of photothermal therapy (PTT) is often hampered by the thermo-resistance of tumor cells mediated by over-expressed heat shock proteins (HSPs). Herein, we developed a guanidine-rich, spherical helical polypeptide (DPP) with multivalency-assisted strong membrane penetrating capability, which mediated effective RNAi against tumor glycolysis metabolism to sensitize PTT. ICG was loaded into the internal cavity of DPP, and siRNA against pyruvate kinase M2 (siPKM2) was condensed by DPP to form positively charged nanocomplexes (NCs). The NCs were further coated with human serum albumin to enhance serum stability, prolong blood circulation, and improve tumor targeting. Due to its multivalent topology, DPP exhibited stronger membrane activity yet lower cytotoxicity than its linear analogue (LPP), thus enabling efficient PKM2 silencing in MCF-7 cells in vitro (~75%) and in vivo (~70%). The PKM2 silencing inhibited tumor glycolysis metabolism and further depleted the energy supply for HSPs production, thus overcoming the heat endurance of tumor cells to strengthen ICG-mediated photothermal ablation. Additionally, siPKM2-mediated energy depletion led to tumor cell starvation, which imparted synergistic anti-cancer effect with PTT. This study therefore provides a promising strategy for designing membrane-penetrating siRNA delivery materials, and it renders a unique RNAi-mediated anti-metabolic mechanism in sensitizing PTT and enabling starvation therapy.