Intelligent Thermo‐Self‐Limited Magnetothermia with Heat‐Triggered TERT Silencing for Precision Synergetic Cancer Therapy

The combination of hyperthermal therapy and gene therapy (GT) has emerged as a promising strategy for cancer treatment. However, the overheating damage and complex temperature control procedure in hyperthermal therapy, along with the limited precision of GT, greatly compromise the therapeutic effectiveness. In this study, a novel nanoplatform (IONP@H₁THs) was rationally designed and fabricated by integrating ultra-small iron oxide nanoparticles with functional DNAs, featuring self-limiting magnetothermal performance and heat-induced precision target gene editing for mild-thermal therapy (MTT) and GT synergetic cancer treatment. Upon binding to telomerase reverse transcriptase (TERT) mRNA, the hairpin DNA within IONP@H₁THs initiates self-assembly through hairpin DNA-mediated dimer formation, thereby enhancing magnetothermal properties of IONP@H₁THs in cancer cells specifically. Upon heating to a specified temperature of the assembled IONP@H₁THs, the temperature-sensitive double-stranded DNA unwinds partially into single strands, resulting in reduced magnetic heating capacity and achieving a balance between heating and scattering, which enables self-limited heating for MTT. Simultaneously, the mild thermal conditions activate transcription from the Hsp70 promoter, inducing in situ small interfering RNA synthesis for TERT gene knockdown to synergize with MTT-mediated cancer treatment. Overall, this approach represents a promising strategy for tumor therapy by integrating thermo-self-limited MTT with heat-triggered precise GT.