Bio-nanocomplexes impair iron homeostasis to induce non-canonical ferroptosis in cancer cells.

The targeted elevation of the labile iron pool (LIP) represents the most direct and effective strategy to induce ferroptosis in cancer cells. However, the efficiency of increasing LIP to induce ferroptosis via iron supplementation is controversial due to the iron homeostasis between LIP and storage iron pool, leading to poor effects and serious safety concerns. In this study, a bio-nanocomplex named AbDA-Lim, composed of albumin, polydopamine, and limonene, is prepared to promote LIP and induce non-canonical ferroptosis in cancer cells by destroying the iron balance. Albumin avidity drives AbDA-Lim entering cancer cells. Subsequently, the released polydopamine enhances the expression of HMOX1 to degrade haem and facilitate the transformation of Fe (III) to Fe (II). Meanwhile, limonene reduces glutathione (GSH) levels via inhibiting CBS, thereby, triggering the release of Fe (II) into LIP from its GSH-bound storage state. The augmentation of LIP ultimately triggers non-canonical ferroptosis in cancer cells. Furthermore, the photothermal property of polydopamine augments the synergistic anti-tumor efficiency of AbDA-Lim by incorporating photothermal therapy. This study presents a distinctive, cascading, and biotic strategy for promoting LIP non-canonically to induce ferroptosis.