Magnetic hyperthermia (MHT) is a therapeutic modality for the treatment of solid tumors that has now accumulated more than 30 years of experience. In the ongoing MHT clinical trials for the treatment of brain and prostate tumors, iron oxide nanoparticles are employed as intra-tumoral MHT agents under a patient-safe 100 kHz alternating magnetic field (AMF) applicator. Although iron oxide nanoparticles are currently approved by FDA for imaging purposes and for the treatment of anemia, magnetic nanoparticles (MNPs) designed for the efficient treatment of MHT must respond to specific physical–chemical properties in terms of magneto-energy conversion, heat dose production, surface chemistry and aggregation state. Accordingly, in the past few decades, these requirements have boosted the development of a new generation of MNPs specifically aimed for MHT. In this review, we present an overview on MNPs and their assemblies produced via different synthetic routes, focusing on which MNP features have allowed unprecedented heating efficiency levels to be achieved in MHT and highlighting nanoplatforms that prevent magnetic heat loss in the intracellular environment. Moreover, we review the advances on MNP-based nanoplatforms that embrace the concept of multimodal therapy, which aims to combine MHT with chemotherapy, radiotherapy, immunotherapy, photodynamic or phototherapy. Next, for a better control of the therapeutic temperature at the tumor, we focus on the studies that have optimized MNPs to maintain gold-standard MHT performance and are also tackling MNP imaging with the aim to quantitatively assess the amount of nanoparticles accumulated at the tumor site and regulate the MHT field conditions. To conclude, future perspectives with guidance on how to advance MHT therapy will be provided.

Combining hard matter, like inorganic nanocrystals, and soft materials, like polymers, can generate multipurpose materials with a broader range of applications with respect to the individual building blocks. Given their unique properties at the nanoscale, magnetic nanoparticles (MNPs) have drawn a great deal of interest due to their potential use in the biomedical field, targeting several applications such as heat hubs in magnetic hyperthermia (MHT, a heat-damage based therapy), contrast agents in magnetic resonance imaging (MRI), and nanocarriers for targeted drug delivery. At the same time, polymers, with their versatile macromolecular structure, can serve as flexible platforms with regard to constructing advanced functional materials. Advances in the development of novel polymerization techniques has enabled the preparation of a large portfolio of polymers that have intriguing physicochemical properties; in particular, those polymers that can undergo conformational and structural changes in response to their surrounding environmental stimuli. Therefore, merging the unique features of MNPs with polymer responsive properties, such as pH and thermal stimuli activation, enables smart control of polymer properties operated by the MNPs and vice versa at an unprecedented level of sophistication. These magnetic-stimuli-responsive nanosystems will impact the cancer field by combining magnetic hyperthermia with stimuli-dependent controlled drug delivery toward multimodal therapies. In this approach, a malignant tumor may be destroyed by a combination of the synergic effects of thermal energy generated by MNPs and the controlled release of antitumoral agents, activated by means of either heat or pH changes, finally leading to a much more effective cancer treatment than those available today. Also, taking advantage of such a triggered chemotherapy will overcome the notorious drawbacks of classic chemotherapy. Nevertheless, tracking the changes in the magnetic properties of such pH-responsive magnetic nanoparticles, which are provided by changes in relaxation signals of water molecules surrounding the nanoplatform, is a novel approach to the detection of pathological conditions (such as pH-changes at the ischemic and tumor sites). Despite great efforts by chemists to fabricate different featured materials, there have been few successful preclinical studies to date. A clinical translation of magnetic stimuli-responsive systems would require overcoming the actual nanosystem limitations and the joint efforts of an interdisciplinary scientific community. In this Account, we have framed state of the art magnetic stimuli-responsive systems, focusing on thermo- and pH-responsive behavior, following an organization based on the response mechanisms of polymers. By evaluating the features of the most representative and advanced nanosystems that already exist in literature, we present the challenges to overcome, the future directions to undertake for the development of magnetic stimuli-responsive nanoplatforms that will work under clinical operating conditions and have biodegradable and biocompatible features, and a consideration of the technical aspects.

We report a highly reproducible route to synthesize iron oxide nanoparticles (IONPs) with control over size and shape and with size dispersions around 10%. By tuning the relative ratio of squalane to dibenzyl ether, which were used as solvents in the synthesis, the size of the particles could be varied from 14 to around 100 nm, while their shape evolved from cubic (for size ranges up to 35 nm) to truncated octahedra and octahedra (for sizes from 40 nm up to 100 nm). Fine tuning of the size within each of these ranges could be achieved by varying the heating ramp and the iron precursor to decanoic acid ratio. We also demonstrate direct water transfer of the as-synthesized IONPs via in situ ligand exchange with gallol polyethylene glycol molecules, the latter simply added to the crude nanocrystal mixture at 70 °C. The specific absorption rate (SAR) values measured on the water transferred IONPs, at frequencies and applied magnetic fields that are considered safe for patients, confirmed their high heating performance. Finally, this method allows the transfer of 35 nm nanocubes as individually coated and stable particles to the water phase. For the first time, the heating performance of such large IONPs has been studied. This work uncovers the possibility of using large IONPs for magnetic hyperthermia in tumor therapy.

Nanoparticle‐based magnetic hyperthermia is a well‐known thermal therapy platform studied to treat solid tumors, but its use for monotherapy is limited due to incomplete tumor eradication at hyperthermia temperature (45 °C). It is often combined with chemotherapy for obtaining a more effective therapeutic outcome. Cubic‐shaped cobalt ferrite nanoparticles (Co–Fe NCs) serve as magnetic hyperthermia agents and as a cytotoxic agent due to the known cobalt ion toxicity, allowing the achievement of both heat and cytotoxic effects from a single platform. In addition to this advantage, Co–Fe NCs have the unique ability to form growing chains under an alternating magnetic field (AMF). This unique chain formation, along with the mild hyperthermia and intrinsic cobalt toxicity, leads to complete tumor regression and improved overall survival in an in vivo murine xenograft model, all under clinically approved AMF conditions. Numerical calculations identify magnetic anisotropy as the main Co–Fe NCs’ feature to generate such chain formations. This novel combination therapy can improve the effects of magnetic hyperthermia, inaugurating investigation of mechanical behaviors of nanoparticles under AMF, as a new avenue for cancer therapy.

We describe the colloidal hot-injection synthesis of phase-pure nanocrystals (NCs) of a highly abundant mineral, chalcopyrite (CuFeS₂). Absorption bands centered at around 480 and 950 nm, spanning almost the entire visible and near-infrared regions, encompass their optical extinction characteristics. These peaks are ascribable to electronic transitions from the valence band (VB) to the empty intermediate band (IB), located in the fundamental gap and mainly composed of Fe 3d orbitals. Laser-irradiation (at 808 nm) of an aqueous suspension of CuFeS₂ NCs exhibited significant heating, with a photothermal conversion efficiency of 49%. Such efficient heating is ascribable to the carrier relaxation within the broad IB band (owing to the indirect VB–IB gap), as corroborated by transient absorption measurements. The intense absorption and high photothermal transduction efficiency (PTE) of these NCs in the so-called biological window (650–900 nm) make them suitable for photothermal therapy as demonstrated by tumor cell annihilation upon laser irradiation. The otherwise harmless nature of these NCs in dark conditions was confirmed by in vitro toxicity tests on two different cell lines. The presence of the deep Fe levels constituting the IB is the origin of such enhanced PTE, which can be used to design other high performing NC photothermal agents.