Ferritin-Inspired Mineralized Iron Phosphate Nanominerals for Precision Ferroptosis-Immunotherapy via Controlled Iron Storage and Release.

Abstract

Ferroptosis provides promising method for tumor therapy but is limited by the low efficiency and safety concerns of conventional iron delivery systems. Herein, we report efficient ferritin-mimetic nanominerals engineered via a small molecule-mediated iron phosphate mineralization strategy, which emulates the natural iron storage and release processes to selectively trigger tumor ferroptosis. Using two ferroptosis inducers, palbociclib and Fin56, as model small molecules, the resulting nanominerals exhibit uniform size distribution, robust stability, and 72% iron incorporation efficiency, enabling precisely controlled ferrous ion release and dual-drug co-delivery within tumor tissues to achieve a triple amplification of ferroptosis. The amplified ferroptosis response further elicits a potent antitumor immune effect through immunogenic cell death, ultimately resulting in remarkable therapeutic efficacy with minimal side effects both in vitro and in vivo. This small molecule-mediated iron phosphate mineralization strategy offers a superior alternative to traditional coordination self-assembly for nanomedicine construction through enhanced programmability, improved stability and higher iron loading, thereby advancing ferroptosis-related combination therapy and synergistic therapy.