Intelligent Self-amplifying Ferroptosis-inducible nanoplatform for enhanced tumor microenvironment reconstruction and combination therapy

As an approved chemotherapeutic drug for breast cancer (BC) therapy, the continuous application of doxorubicin (DOX) is unfortunately limited by its poor selectivity and the apoptosis resistance of tumor cells. To cope with the obstacles, this work developed a tumor-specific nanoplatform (named p-LDM) for DOX delivery and combinational ferroptosis-apoptosis activation. p-LDM was fabricated by coating ferric metal–organic framework (MOF) with liposomes and the outer liposomal membrane was further interspersed with targeting peptide-conjugated enzyme-activatiable cell-penetrating peptides (CPPs) to guarantee the tumor-specific penetration. As two components of the MOF core, Fe3+ (metal ion junction) triggered the ferroptosis of 4T1 cells via its self-cyclic valence alteration and terephthalic acid (H2BDC, organic ligand) reinforced the Fe3+-triggered ferroptosis by inhibiting carbonic anhydrase IX (CA IX); this self-amplifying strategy delicately boosted robust tumor ferroptosis. By combining DOX and ferroptosis activation, p-LDM performed forceful direct killing effect, immungentic cell death (ICD) stimulation, T cell activation and dendritic cell (DC) maturation promotion, suggesting its potential for synergetic apoptosis/ferroptosis activation and tumor immune microenvironment (TIM) remodeling. Further, p-LDM was combined with CD47-SIRPα blockade therapy, generating reinforced ferroptosis, which was largely attributed to the maximal up-regulation of IFN-γ levels and consequent system Xc- inhibition. Besides, the released "find me" signal from ferroptosis, "eat me" signal from ICD and the inhibited CD47-released "don't eat me" signal jointly remodeled the suppressive TIM, receiving superior synergistic inhibitions on tumor growth, metastasis and recurrence.