Alginate/PEG-Fe₃O₄ hydrogel augmented cryoablation for synergistic tumor suppression

Cryoablation (here after referred to as CA) is a minimally invasive anticancer therapy that utilizes extreme low temperatures induced by external energy intervention. However, the temperature gradient generated during the procedure compromises therapeutic efficacy by impeding the formation of sufficient ice crystals at the tumor margins. To address this limitation, we developed a novel combinatorial strategy integrating CA with a multifunctional drug delivery system composed of polyethylene glycol (PEG)-modified Fe₃O₄ nanoparticles (PEG-Fe₃O₄) embeddedin a sodium alginate (ALG) matrix (ALG-PEG-Fe₃O₄). Once injecting into tumor tissues, ALG and calcium can quickly crosslink to form hydrogel in situ, which effectively fixed PEG-Fe₃O₄ within the tumor tissue. The high thermal conductivity of PEG-Fe₃O₄ facilitated efficient heat dissipation, overcoming the temperature gradient-induced suppression of ice crystal formation at the tumor margin during CA. Our results demonstrated that the combined CA+ALG-PEG-Fe₃O₄ therapy induced significant mitochondrial and cell membrane disruption, leading to suppressed oxidative phosphorylation and glycolysis inhibition. This dual metabolic interference caused severe cellular energy depletion and elevated reactive oxygen species (ROS) production, effectively triggering extensive tumor cell apoptosis and markedly enhanced antitumor efficacy.