This review focuses on the latest advancements in magnetic hydroxyapatite (mHA) nanoparticles and their potential applications in nanomedicine and regenerative medicine. mHA nanoparticles have gained significant interest over the last few years for their great potential, offering advanced multi-therapeutic strategies because of their biocompatibility, bioactivity, and unique physicochemical features, enabling on-demand activation and control. The most relevant synthetic methods to obtain magnetic apatite-based materials, either in the form of iron-doped HA nanoparticles showing intrinsic magnetic properties or composite/hybrid compounds between HA and superparamagnetic metal oxide nanoparticles, are described as highlighting structure–property correlations. Following this, this review discusses the application of various magnetic hydroxyapatite nanomaterials in bone regeneration and nanomedicine. Finally, novel perspectives are investigated with respect to the ability of mHA nanoparticles to improve nanocarriers with homogeneous structures to promote multifunctional biological applications, such as cell stimulation and instruction, antimicrobial activity, and drug release with on-demand triggering.

Breast cancer (BC) frequently metastasizes to bone, leading to poor patient prognosis. The infiltration of cancer cells in bone impairs its homeostasis, triggering a pathological interaction between tumors and resident cells. Preclinical models able to mimic the bone microenvironment are needed to advance translational findings on BC mechanisms and treatments. We designed strontium-doped calcium phosphate cement to be employed for culturing cancer and bone cells and developed an in vitro bone metastasis model. The platform was established step by step, starting with the monoculture of cancer cells, mature osteoblasts (OBs) differentiated from mesenchymal stem cells, and mature osteoclasts (OCs) differentiated from Peripheral Blood Mononuclear Cells. The model was implemented with the co-culture of cancer cells with OBs or OCs, or the co-culture of OBs and OCs, allowing us to discriminate the interaction between the actors of the bone metastatic niche. The biomimetic material was further challenged with bone metastasis patient-derived material, showing good versatility and biocompatibility, suggesting its potential use as bone substitute. Overall, we developed a bone-mimicking model able to reproduce reciprocal interactions between cancer and bone cells in a biomimetic environment suitable for studying the biomolecular determinants of bone metastasis and, in the future, as a drug efficacy platform.

Small interfering RNAs (siRNAs) are particularly attractive among the frontier drugs due to their high specificity of action, activity on disease-inducing genes, and small molecular weight, thus being one of the most studied agents for gene therapy. However, siRNAs are prone to fast enzymatic degradation in the bloodstream, as well as other limitations that challenge their clinical translation. Nanoparticle (NP) delivery of siRNA has been proposed as a potential solution, overcoming their intrinsic limitations. In this regard, the siRNA delivery by magnetic nanoparticles is of particular interest because, being susceptible to external magnetic fields, it may be guided remotely, maximizing transfection efficiency and minimizing side effects. In addition, magnetic NPs would also allow a theranostic combination of drug delivery, magnetic resonance imaging, and hyperthermia. In this work we have studied the uptake of a model therapeutic siRNA by iron-doped hydroxyapatite nanoparticles (FeHA NPs), which are known to have excellent biocompatibility and magnetic susceptibility. We discovered that FeHA NPs stabilized by citrate (Cit-FeHA NPs) uptake siRNA by adsorption quickly and with high efficiency (ca. 90%) without altering nanoparticles physicochemical properties or colloidal stability. SiRNA-loaded Cit-FeHA NPs are able to slowly release their payload, with a sustained release of 45 days without siRNA degradation. Our work is therefore the preliminary validation of the suitability of FeHA NPs for magnetically guided delivery of therapeutic siRNAs.

The degeneration of osteochondral tissue represents one of the major causes of disability in modern society and it is expected to fuel the demand for new solutions to repair and regenerate the damaged articular joints. In particular, osteoarthritis (OA) is the most common complication in articular diseases and a leading cause of chronic disability affecting a steady increasing number of people. The regeneration of osteochondral (OC) defects is one of the most challenging tasks in orthopedics since this anatomical region is composed of different tissues, characterized by antithetic features and functionalities, in tight connection to work together as a joint. The altered structural and mechanical joint environment impairs the natural tissue metabolism, thus making OC regeneration even more challenging. In this scenario, marine-derived ingredients elicit ever-increased interest for biomedical applications as a result of their outstanding mechanical and multiple biologic properties. The review highlights the possibility to exploit such unique features using a combination of bio-inspired synthesis process and 3D manufacturing technologies, relevant to generate compositionally and structurally graded hybrid constructs reproducing the smart architecture and biomechanical functions of natural OC regions.

The present work investigates the rheological behavior of ceramic slurries made of hydroxyapatite powders doped with magnesium and strontium ions and selected as particularly relevant for biomedical applications. The incorporation of doping ions into the apatite crystal structure is a well-known way to enhance the bioactivity of hydroxyapatite through compositional and structural changes, however, this also affects the rheological properties relevant to the fabrication of ceramic devices by forming techniques based on the manipulation of aqueous slurries. We analyzed the effect of different apatitic chemical compositions, powder content, and dispersant amount on the shear behavior and flowability of slurries, thus finding that the structural changes in hydroxyapatite induced by ion doping significantly affected the colloidal stability of the apatite powders and the viscoelasticity of the slurries. This leads to improved rheological behavior in the hydroxyapatite suspensions, which is suitable for the future development of ceramic slurries, particularly for achieving novel ceramic devices by extrusion-based techniques.

Small interfering RNAs (siRNAs) provide strong therapeutic potential due to their efficient gene-silencing properties; however, their instability limits clinical application. Nanoparticle carriers may overcome this problem; in particular, magnetic nanoparticles show great promise as they can be directed to the target sites by external magnetic fields, thus improving delivery efficiency and reducing off-target effects. In addition, magnetic nanoparticles offer a novel nanoplatform for theranostic applications, integrating siRNA delivery with magnetic resonance imaging and magnetic hyperthermia for synergistic diagnostic and therapeutic advantages. The present work reports the development of a novel platform based on biomimetic magnetic nanoparticles made of Fe(II)/Fe(III)-doped apatite (FeHA) nucleated and grown in the presence of cherry and pomegranate leaf extracts to enhance the colloidal stability and make it suitable for nucleic acid delivery under the guidance of magnetic fields. This approach allowed the obtention of FeHA suspension with increased negative zeta potential leading to very good stability. In addition, the functionalization with natural extracts conferred antioxidant properties also favoring the maintenance of the Fe(III)/Fe(II) ratio in the apatitic structure, inducing the superparamagnetic properties. To evaluate the delivery capability of the system, a model GAPDH-targeting siRNA molecule was employed. Its interaction with the nanoplatform was characterized by assessing loading capacity and release kinetics, which were further interpreted using mathematical modeling to elucidate the underlying release mechanisms.