Akira Ito

1. Living systems provide unique functions, such as environmental responsiveness, self-maintenance, and metabolism, which are difficult to replicate using artificial materials. There is growing int...

Magnetic hyperthermia, in which magnetic nanoparticles (MNPs) generate heat under an alternating magnetic field, has emerged as a promising strategy for cancer therapy. Among numerous magnetic hyperthermia platforms, direct intratumoral administration has achieved the greatest clinical progress because it enables localized heat generation while overcoming the limited tumor accumulation associated with systemic nanoparticle delivery. The development of functional MNPs capable of efficient cellular interaction and intracellular localization has further expanded magnetic hyperthermia beyond conventional tissue heating toward intracellular hyperthermia and cancer immunotherapy. This review summarizes the historical evolution and clinical translation of functional MNPs with particular emphasis on the design principles that have facilitated successful clinical development. We discuss how advances in nanoparticle engineering have improved intratumoral retention, intracellular delivery, thermal dose optimization, and therapeutic efficacy. We further review the emerging role of magnetic hyperthermia as an in situ vaccination strategy capable of inducing immunogenic cell death and stimulating systemic antitumor immunity, providing a biological rationale for combination with immunotherapies. Finally, we discuss current challenges limiting widespread clinical translation, together with future perspectives on multifunctional therapeutic and theranostic nanoplatforms. These advances position functional MNPs as promising platforms for next-generation cancer therapy.

Magnetic hyperthermia is a therapeutic strategy for cancer that utilizes the heat generated by magnetic nanoparticles exposed to an alternating magnetic field (AMF) to locally elevate tumor tissue temperature and induce cancer cell death. Effective treatment requires delivering an adequate amount of magnetic nanoparticles to the tumor. However, systemic administration is often constrained by insufficient tumor accumulation and potential safety concerns arising from off-target biodistribution, thereby hindering clinical translation. Although direct intratumoral administration can mitigate these limitations, nanoparticles may still rapidly diffuse or leak from the injection site, resulting in insufficient intratumoral retention. In this study, we engineered magnetite nanoparticles (MNPs) to enhance intratumoral retention in HER2-positive tumors via antibody-mediated interactions. Poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) brushes were grafted onto the surface of MNPs, followed by conjugation of the anti-HER2 antibody trastuzumab (Tmab), yielding antibody-modified nanoparticles (MNPs−PMPC−Tmab). In vitro experiments demonstrated increased cellular association of MNPs−PMPC−Tmab with HER2-positive cells compared with HER2-negative counterparts. Following intratumoral administration in nude mice bearing HER2-positive NCI-N87 tumors, MNPs−PMPC−Tmab exhibited higher intratumoral retention than non-antibody-modified controls and remained detectable for up to 72 h. Upon AMF exposure, these nanoparticles elevated tumor temperature to 46 °C and successfully suppressed tumor growth. Collectively, these results demonstrate that surface engineering integrating an antifouling polymer brush with a tumor-targeting antibody is an effective strategy for improving intratumoral retention of magnetic nanoparticles and enhancing therapeutic performance in magnetic hyperthermia.

Bladder cancer (BC) often arises in an immunosuppressive tumor microenvironment that limits responses to immune checkpoint inhibitors. Magnetic hyperthermia therapy (MHT) can induce immunogenic cell death, but its value as an immunotherapeutic remains insufficient. We conjugated anti-programmed death-ligand 1 (PD-L1) antibody (αPD-L1) with magnetite cationic liposomes (MCL) and developed αPD-L1@MCL for MHT in an MB49 murine subcutaneous BC model. Mice received a single or triple exposure of αPD-L1@MCL-mediated MHT (P-MHT) at 43 °C or 46 °C (n = 5 per group), then we assessed tumor growth and CD8⁺ T-cell infiltration. Without αPD-L1, triple MHT at 46 °C induced complete tumor regression, whereas a single exposure 43 °C was insufficient. A single exposure 43 °C P-MHT achieved complete regression in four out of five mice. Flow cytometry revealed an increase in CD8⁺ T cells in tumors treated with P-MHT. Our αPD-L1@MCL enables hyperthermia with magnetic nanoparticles and immunotherapy with an anti-PD-L1 antibody. These findings support further development of hyperthermia mediated by anti-PD-L1 antibody-conjugated magnetic nanoparticles as a promising therapeutic strategy for BC.

Magnetic nanoparticle (MNP)-mediated hyperthermia is a promising approach for cancer therapy because it enables the local heating and killing of tumor cells. The systemic administration of MNPs via intravenous injection is crucial for the treatment of a wide range of cancers, including deep-seated tumors. However, the clinical translation of this technology is severely hampered by the extremely low efficiency of nanoparticle delivery to tumor tissues, which has been a major bottleneck limiting therapeutic efficacy. This review provides an overview of recent advances in strategies to overcome this challenge. We first discuss conventional drug delivery system approaches based on the enhanced permeability and retention effect, and then highlight key preclinical studies demonstrating the trend towards developing functional MNPs. Moreover, we explored emerging paradigms, such as the strategic manipulation of nanoparticle-blood protein interactions (protein corona formation) to control the in vivo biodistribution of nanoparticles and the recently proposed active transport and retention principle. Furthermore, we introduce strategies to maximize the local therapeutic efficacy once MNPs reach the tumor, including MNP-based platforms for controlled drug release, subcellular targeting of mitochondria, and the combination of hyperthermia with immunotherapy. The clinical success of magnetic hyperthermia depends on improving nanoparticle delivery to tumors based on a deeper understanding of biological interactions and enhancing the local therapeutic effect.

Cancer hyperthermia induced through magnetic nanoparticles that generate heat upon irradiation with an alternating magnetic field (AMF) allows local heating of tumor tissues, leading to cancer cell death. For the clinical application of magnetic nanoparticles, designing an appropriate surface structure is important for maintaining colloidal stability and stealth properties that prevent clearance by the mononuclear phagocyte system. Catechol-containing polymers offer stable modification and functionalization of nanoparticles. However, the effect of their molecular structure on the modification efficiency and function of nanoparticles remains unclear. Herein, magnetite nanoparticles (MNPs) modified with a series of catechol-containing polymers composed of dopamine methacrylamide (DMA) units and biocompatible phosphorylcholine units were prepared. Higher molecular weights of the polymers resulted in higher modification amounts on the MNPs, whereas the DMA unit content had little impact. Modifying the polymers improved the dispersion stability of the MNPs in phosphate-buffered saline and their stealth property against macrophages in vitro. Polymers with more than 1.8 mol % DMA units enabled stable dispersion of MNPs for 14 days. Modifying the polymers with DMA unit contents between 4.8 and 9.0 mol % minimized the macrophage uptake of the MNPs. Moreover, the polymer-modified MNPs were loaded with the anticancer drug bortezomib, and the release of bortezomib was enhanced by irradiation with an AMF for magnetic hyperthermia. In vitro magnetic hyperthermia with polymer-modified MNPs successfully killed mouse colon cancer cells, and bortezomib loading augmented the anticancer activity. This study will provide crucial guidance on the molecular design of catechol-containing polymers for effective cancer hyperthermia using magnetic nanoparticles.

Hyperthermia using magnetic nanoparticles is a promising cancer therapy that locally destroys tumors and induces antitumor immunity by releasing tumor antigens from dying cells. However, magnetic hyperthermia in malignant melanomas with poor immunogenicity and an immunosuppressive microenvironment remains challenging. Here, all‐in‐one magnetic nanoparticles (αPD‐L1/CpG@MCL) are developed for thermo‐immunotherapy that enables hyperthermia with magnetic nanoparticles and immunotherapy with anti‐PD‐L1 antibody and CpG to improve the immunosuppressive tumor microenvironment. Magnetic hyperthermia with magnetite cationic liposomes (MCL, without anti‐PD‐L1 antibody and CpG) inhibits tumor growth in B16F10 melanoma; however, complete tumor regression is not observed. In contrast, complete tumor regression is observed when mice are treated with thermo‐immunotherapy using αPD‐L1/CpG@MCL. Additionally, mice cured after magnetic hyperthermia with αPD‐L1/CpG@MCL rejected rechallenge with B16F10 cells, and cytotoxicity assay using splenocytes from cured mice shows the induction of antitumor immunity against B16F10 cells. Analysis of tumor‐infiltrating lymphocytes reveals that magnetic hyperthermia with αPD‐L1/CpG@MCL increased CD8⁺ T lymphocytes and M1‐like macrophages, and decreased M2‐like macrophages, indicating an improvement in the tumor microenvironment. This study provides a key design strategy for all‐in‐one magnetic nanoparticles that could cure malignant melanomas.

Magnetite (Fe3O4) nanoparticles have been clinically used as MRI contrast agents and are known as highly biocompatible magnetic nanoparticles. The magnetic nanoparticles have been applied to medical fields since they are attracted to magnetic fields and also generate heat in an alternating magnetic field. In this review, we introduce our research on "magnetic pattering of cells", "skeletal muscle tissue engineering using magnetic force", and "nanowarming" as a technology for thawing frozen cells using magnetic particles.

Since magnetic nanoparticles generate heat in a high–frequency alternating magnetic field, researchers have conducted magnetic hyperthermia, in which magnetic nanoparticles are delivered to tumors and magnetic–field– induced heating is used to destroy the tumor. If magnetic nanoparticles can be delivered to tumors, tumors can be heated by irradiating an alternating magnetic field from outside the body, enabling specific hyperthermia to kill only cancer cells with heat. The authors have previously produced magnetite cationic liposomes in which magnetic nanoparticles are embedded in liposomes made of positively charged lipids, antibody–conjugated magnetite nanoparticles in which antibody drugs are bound to the surface of magnetic nanoparticles, and mitochondria–targeted magnetite nanoparticles in which magnetic nanoparticles are coated with a polymer containing a compound that specifically accumulates in mitochondria. In addition, we have developed melanoma–targeted magnetite nanoparticles in which NPrCAP, a drug that molecularly targets the mechanism by which melanoma is bound to magnetic nanoparticles. In this paper, we will describe these functional magnetic nanoparticles and discuss the future prospects.