Efficient delivery of DMDD by an iron-engineered mesoporous organosilica nanoplatform reshapes the breast cancer immune microenvironment via autophagy activation and immune checkpoint modulation

Breast cancer is the most common malignancy worldwide. Patients with advanced disease often experience recurrence and metastasis, driven by the immunosuppressive tumor microenvironment and resistance to PD‑1/PD‑L1 checkpoint therapy. To address these challenges, we developed a multifunctional nanoplatform named DMDD@MON‑Fe that integrates autophagy induction, immune modulation, and efficient therapy, and systematically evaluated its anti‑tumor efficacy and molecular mechanisms in breast cancer. Mesoporous organosilica nanoparticles (MON) were prepared using a one-pot template method. Iron species were introduced into MON through a heating-sublimation strategy to obtain MON-Fe, which was subsequently loaded with the natural small-molecule compound DMDD to form DMDD@MON-Fe. The nanoparticles were characterized by TEM, SEM, XPS, DLS, and BET. Their effects on breast cancer cell proliferation, migration, invasion, cell cycle, apoptosis, ROS, autophagy, and PD-L1/PD-1 expression were examined using MTT, colony formation, Transwell, flow cytometry, MDC staining, Western blot, and immunofluorescence. In vivo anti-tumor efficacy was evaluated in a subcutaneous syngeneic tumor model, and mechanisms and biosafety were explored via transcriptome sequencing, RT-qPCR, immunohistochemistry, TEM, and blood biochemical analysis. DMDD@MON-Fe showed a spherical morphology, pH-responsive drug release, and good hemocompatibility. In vitro, it significantly inhibited breast cancer cell proliferation, migration, and invasion, induced cell-cycle arrest, and promoted apoptosis and ROS generation. Mechanistically, DMDD@MON-Fe downregulated the PI3K/Akt/mTOR protein expression, activated autophagy, and suppressed PD-L1/PD-1 expression as shown by Western blot and immunofluorescence. In vivo, it inhibited tumor growth and induced autophagy and chromatin condensation (TEM). Transcriptomics revealed enrichment of differentially expressed genes in PI3K-Akt, autophagy, and immune-related pathways. H&E staining and liver/kidney function tests confirmed excellent biosafety. DMDD@MON-Fe represents a promising iron-engineered mesoporous organosilica nanoplatform for enhancing DMDD delivery and antitumor efficacy in breast cancer. Its therapeutic effects are associated with increased ROS generation, suppression of PI3K/Akt/mTOR signaling, activation of autophagy, and inhibition of PD-L1 expression. These findings provide a potential nanomedicine-based strategy for improving DMDD delivery and alleviating PD-L1-associated immune suppression in breast cancer.