Force-Mediated Endocytosis of Iron Oxide Nanoparticles for Magnetic Targeting of Stem Cells.

Stem cell therapy represents one of the most promising approaches for tissue repair and regeneration. However, the full potential of stem cell therapy remains to be realized. One major challenge is the insufficient homing and retention of stem cells at the desired sites after in vivo delivery. Here, we provide a proof-of-principle demonstration of magnetic targeting and retention of human muscle-derived stem cells (hMDSCs) in vitro through magnetic force-mediated internalization of magnetic iron oxide nanoparticles (MIONs) and the use of a micropatterned magnet. We found that the magnetic force-mediated cellular uptake of MIONs occurs through an endocytic pathway, and the MIONs were exclusively localized in the lysosomes. The intracellular MIONs had no detrimental effect on the proliferation of hMDSCs or their multilineage differentiation, and no MIONs were translocated to other cells in a coculture system. Using hMDSCs and three other cell types including human umbilical vein endothelial cells (HUVECs), human dermal fibroblasts (HDFs), and HeLa cells, we further discovered that the magnetic force-mediated MION uptake increased with MION size and decreased with cell membrane tension. We found that the cellular uptake rate was initially increased with MION concentration in solution and approached saturation. These findings provide important insight and guidance for magnetic targeting of stem cells in therapeutic applications.

Multifunctional Magnetic Nanoclusters Can Induce Immunogenic Cell Death and Suppress Tumor Recurrence and Metastasis.

Metastasis is the predominant cause of cancer deaths due to solid organ malignancies; however, anticancer drugs are not effective in treating metastatic cancer. Here we report a nanotherapeutic approach that combines magnetic nanocluster-based hyperthermia and free radical generation with an immune checkpoint blockade (ICB) for effective suppression of both primary and secondary tumors. We attached 2,2'-azobis(2-midinopropane) dihydrochloride (AAPH) molecules to magnetic iron oxide nanoclusters (IONCs) to form an IONC-AAPH nanoplatform. The IONC can generate a high level of localized heat under an alternating magnetic field (AMF), which decomposes the AAPH on the cluster surface and produces a large number of carbon-centered free radicals. A combination of localized heating and free radicals can effectively kill tumor cells under both normoxic and hypoxic conditions. The tumor cell death caused by the combination of magnetic heating and free radicals led to the release or exposure of various damage-associated molecule patterns, which promoted the maturation of dendritic cells. Treating the tumor-bearing mice with IONC-AAPH under AMF not only eradicated the tumors but also generated systemic antitumor immune responses. The combination of IONC-AAPH under AMF with anti-PD-1 ICB dramatically suppressed the growth of untreated distant tumors and induced long-term immune memory. This IONC-AAPH based magneto-immunotherapy has the potential to effectively combat metastasis and control cancer recurrence.