Focused ultrasound-mediated drug delivery systems: a technological overview, possible musculoskeletal applications, and future directions

Abstract

Background

Innovation in focused ultrasound (FUS) has led to new applications for treating musculoskeletal pathologies, including oncologic, infectious, and degenerative diseases. Focused ultrasound-mediated drug delivery is particularly interesting in fields in which high selectivity and localized action are needed to avoid unwanted side effects or therapy failure, for example with antineoplastic and antimicrobial drugs.

Method

For this paper, a literature search of the PubMed database was performed using the keywords “focused ultrasound” and “musculoskeletal applications”.

Conclusion

This review article presents an overview of the currently available technologies for focused ultrasound-mediated drug delivery and their possible musculoskeletal applications, along with a discussion of recent promising preclinical and clinical results.

Key Points

• Focused ultrasound is able to deliver drugs in a very selective way.

• Focused ultrasound-mediated hyperthermia may be promising for treating bone infections.

• Focused ultrasound-mediated drug delivery may also be an elegant method for treating bone cancer and arthritis.

Citation Format

• Sassi R, Gazzotti S, Aparisi Gómez MP et al. Focused ultrasound-mediated drug delivery systems: a technological overview, possible musculoskeletal applications, and future directions. Rofo 2025; DOI 10.1055/a-2760-5392

Zusammenfassung

Hintergrund

Innovationen im Bereich des (hochintensiven) fokussierten Ultraschalls (FUS) haben zu neuen Anwendungen bei der Behandlung von Erkrankungen des Bewegungsapparats geführt, darunter onkologische, infektiöse und degenerative Erkrankungen. Die Verabreichung von Medikamenten mittels FUS ist besonders in den Bereichen interessant, in denen eine hohe Selektivität und lokalisierte Wirkung erforderlich sind, um unerwünschte Nebenwirkungen oder Therapieversagen zu vermeiden, beispielsweise bei antineoplastischen und antimikrobiellen Medikamenten.

Methodik

Eine Literatursuche wurde mittels der PubMed-Datenbank durchgeführt, wobei als primäre Schlüsselwörter „focused ultrasound“ und „musculoskeletal applications“ verwendet wurden. Anschließend wurde die Suche pro Unterthema verfeinert, indem das Schlüsselwort „drug delivery“, verknüpft mit Begriffen „cancer“, „bone cancer“, „bone infections“, „antibiotics“ und „osteoarthritis“, hinzugefügt wurde.

Schlussfolgerung

Dieser Übersichtsartikel bietet einen Überblick über die derzeit verfügbaren Technologien für die Verabreichung von Medikamenten mittels FUS und ihre möglichen Anwendungen am Bewegungsapparat sowie eine Diskussion der jüngsten vielversprechenden präklinischen und klinischen Ergebnisse.

Kernaussagen

• (Hochintensiver) Fokussierter Ultraschall kann Medikamente sehr selektiv verabreichen.

• Hyperthermie mit FUS könnte bei der Behandlung von Knocheninfektionen vielversprechend sein.

• Die Verabreichung von Medikamenten mit FUS könnte auch eine elegante Methode zur Behandlung von Knochenmalignomen und der Arthritis sein.

Keywords

Drug delivery systems - Thermal ablation - Sonoporation - Musculoskeletal application - Focused ultrasound

Introduction

Focused ultrasound (FUS) is a noninvasive technique with a range of different clinical applications, spanning from oncologic treatments to neurological pathologies, and from pain management to innovative drug delivery systems [1]. Imaging has an essential role in guiding treatment. Although ultrasound (US) represents a cost-effective and portable option, magnetic resonance imaging (MRI) remains the gold standard because it allows monitoring of temperature and treatment progress in almost real time and provides a panoramic view of the region of treatment, as well as valuable pre- and post-treatment evaluation [2]. In short, FUS technology exploits the energy released by the passage of either low (LIFU) or high (HIFU) intensity ultrasound waves to target tissues. Tissue damage is achieved by the synergistic combination of two damaging effects: the thermal effect and the cavitation effect, as described in ([Table 1], [Fig. 1] [1] [3] [4] [5] [6] [7] [8] [9]). Depending on the level of FUS intensity, one effect is more prevalent than the other. In fact, at lower intensities (LIFU) acoustic streaming is the most significant mechanism of action, whereas at a higher intensity (HIFU), both heating and acoustic cavitation are equally relevant [2]. Furthermore, the modality by which the impulses are delivered influences the clinical effects. Considering an equal total amount of acoustic energy delivered in the same overall time, continuous sonication is more likely to induce a thermal effect (such as local hyperthermia (HT)) in comparison to repeated sonication at a lower intensity, which results in a greater cavitation effect [3].

Table 1 Description of FUS mechanisms of action and derived properties.

Mechanism of action	Thermal effect	Cavitation effect
Physical principle	Frictional heating: US propagation through tissue layers causes (microscopically) shear motion [3] increasing the temperature Fast temperature increase does not allow heat dissipation through the vasculature [1] Tissue damage volume depends on the time and temperature of exposure [4] (being therapeutically controllable and exploitable)	Cavitation: formation, oscillation, and collapse of microbubbles due to differences in the pressure field within tissues
Biological effect	Thermal necrosis: caused by absorption of US energy rapidly increasing the temperature to more than 55°C; tissues raised to this temperature for more than 1 second undergo coagulative necrosis ([Fig. 1])	Tissue damage [1] by increasing: Pressure Temperature Shear stress Microstreaming jets of liquid
Therapeutic effect	Solid tumor (malignant and benign) ablation: Safe and noninvasive Complements or replaces conventional modalities Enhances chemotherapy Pain palliation (bone metastases) Alternatively or synergically to radiotherapy [5] Focal superficial bone lesions (osteoid osteomas, osteoblastomas) Promising option for soft tissue tumors such as desmoid fibromatosis [6]	Tissue ablation: Thermal necrosis due to increased temperatures Mechanical damage to tissue due to the cavitation Enhancing drug delivery: Frequent microstreaming jets of liquid can provoke sonoporation, forming transient pores in the plasma membrane and increasing cellular permeability [7], potentially enabling crossing of the blood brain barrier (BBB) [8] US contrast agents: by increasing the backscattered signal intensity and, by cyclically cavitating, resonating, generating harmonic frequency detectable by ultrasound imaging probes [9]

Fig. 1 Schematic representation of coagulative necrosis. a) Schematic representation of normal living cells with intact phospholipid membrane. b) Schematic representation of denatured cell membrane due to FUS thermal ablation. c) Schematic representation of necrosis area. Thanks to the high selectivity of the technique, cells are dead only within the targeted area due to coagulative necrosis, while cells remain intact outside of this area.

The urge to find innovative and effective ways of enhancing drug delivery extends from the original central nervous system (CNS) applications to many other pharmaceutical fields such as antimicrobial, antineoplastic, and, more generally, chemotherapy drugs. When referring to such classes of medicines, the need for safety and selectivity becomes crucial, as the side effects of less selective agents have a significant impact both at an individual and a societal level. As new treatment options continue to improve the prognosis in prevalent cancers, like breast, prostate, and colorectal cancer, a new challenge in healthcare is to improve the quality of life of cancer survivors. In this context, greater focus must be given to long-term toxicity and adverse effects of treatments. Therefore, it is essential to be as selective as possible. In many cancer survivors, their disease is at a stage where complete eradication is not possible so that the aim of treatment is to transform the disease into a chronic, possibly inactive condition that is as asymptomatic as possible. One solution to this challenge involves the development of new ways to deliver existing and validated drugs directly to the expected target in order to decrease the side effects of systemic administration and at the same time enhance the local drug concentration and hopefully its action [10].

The scope of the present narrative review is to provide an overview of the available pre-clinical and clinical evidence concerning ultrasound-triggered drug delivery systems, with a particular focus on musculoskeletal applications, as well as to discuss related opportunities and challenges for medical practice.

Materials and Methods

A literature search was performed via the PubMed database in November 2024 using the primary keywords “focused ultrasound” and “musculoskeletal applications”.

Subsequently, the search was refined per sub-topic by adding the keyword “drug delivery” associated with the following terms: “cancer”, “bone cancer”, “bone infections”, “antibiotics” and “osteoarthritis”. Only publications written in English were considered. Furthermore, the search was enhanced using the “snowball” technique, retrieving articles from those cited in the selected articles from the primary search. Although the results included mainly pre-clinical studies and studies with a low evidence level, specific sections on sarcomas, bone infections (in particular, periprosthetic and fracture-related infections), and osteoarthritis were designed with the aim of encouraging further clinical research to boost the therapeutic armamentarium against these highly prevalent and morbid conditions.

Drug delivery systems

In the process of discovering a new therapeutic substance, one of the key issues to solve is how the drug is going to reach the desired target in such a concentration that its pharmaceutical effect will be sufficient to address the pathological status and favorably modify it. It is necessary not only to find the best route of administration but also to modify either the structure of the drug complex itself or the environment in which it is administered. Such technical manipulations fall under the term “drug delivery systems”. The delivery can be modified in terms of both where and when a drug – be it a synthetic molecule or a biological entity – is going to be released [11]. This could be done, for instance by encapsulating it in a carrier of variable size made of a specific material able to respond and adapt to different stimuli, which can be endogenous (like different pHs within the body) or exogenous (like temperature, energy, or magnetic fields). The main disadvantage of the former is the limited controllability, while the latter is more controllable and depends on finding the proper material and stimulus.

It is in this context that FUS has gained interest with regard to drug delivery systems. As briefly introduced above ([Table 1]), FUS acts via multiple effects that can be exploited as different stimuli for triggering drug delivery. When it comes to environmental changes, for instance, FUS can enhance drug permeation by causing mild (HT) and by creating temporary pores in cell membranes through cavitation [12]. As another example of utilizing the thermal effect of FUS, a pre-clinical study showed how a focused increase in temperature could be exploited to trigger thermo-responsive liposome drug delivery systems, increasing the accumulation of the drug in the targeted area [13].

Acoustically active materials and microbubble drug conjugates

Originally, acoustically active micro or nanomaterials were developed as US contrast agents. Simple air bubbles were investigated at the beginning, but their persistence in the bloodstream was extremely limited. Therefore, second-generation agents, containing perfluorocarbon, nitrogen, or more commonly sulfur hexafluoride cores encased in a stabilizing phospholipid shell were proposed [14]. The physical principle behind contrast-enhanced ultrasound (CEUS) is related to the interaction between acoustic energy and microbubbles used as contrast agents. However, when acoustic energy becomes too high, microbubbles may undergo destruction, resulting in the loss of useful diagnostic information. This explains why low mechanical index (MI) settings are generally used in CEUS systems to assess the vascularization of tissues. However, there is a specific technique designed to exploit the destruction of microbubbles for clinical benefit, termed flash imaging, and it is mostly used for the characterization of hepatic lesions. In this case, a pulse with an elevated MI can be activated by the operator to purposefully destroy microbubbles that accumulate in a given region of interest (ROI), thereby annihilating their signal, in order to study the slower refill of the lesion (for instance in the portal venous phase) at the usual low MI settings or to prepare for a re-injection of contrast [15] [16]. In addition to diagnostic ultrasound, bubble bursting can also be used for therapeutic purposes.

By applying higher acoustic pressure, microbubbles become less stable and tend to rapidly grow and then collapse, a phenomenon called “inertial cavitation” [17] ([Fig. 2]). This mechanism can be intrinsically therapeutic, as cavitation itself can cause tissue damage [1] [18], or can be intended as a boost to enhance drug delivery, with microbubbles acting as drug carriers or as cell permeation enhancers [19].

Fig. 2 Cavitation effect. The ultrasound waves cause bubbles to expand and collapse following a sinusoidal scheme, until they would eventually burst when the pressure becomes too high for them to keep steadily cavitating.

Considering the different possibilities regarding drug delivery systems, nanoparticles (NPs) appear to be a promising tool for the improvement of drug stability, solubility, membrane permeation, and safety [20]. When developing the different structures, and depending on their selected application, several parameters need to be appropriately balanced as summarized in ([Table 2] [14] [21] [22] [23] [24] [25] [26]).

Table 2 NP characteristics for drug delivery.

Feature	Effect
Dimensions (1–7µm) and stability [14]	Smaller bubbles: longer lives and ability to circulate in the human bloodstream and permeate the capillary beds [14] Larger bubbles: greater scattering effects [14] Proper size allows permeation and accumulation in the affected tissues while avoiding extravasation into normal tissues to minimize adverse effects [21]
Shape	Round ones have better pharmacodynamic properties Non-spherical NPs could have an increased ability to bind endothelial cells [22]
Charge	Positively charged NPs are more rapidly eliminated from the bloodstream compared to neutral or slightly negative ones Negatively charged NPs are less able to extravasate in healthy tissues [21]
Elasticity	Flexibility elongates in-vivo half-lives decreasing sensitivity to spleen and liver filtration [23]
Coating	Can modulate the rate of elimination from the bloodstream by being: Positively charged Elastic [24] Tailored to enhance: Drug loading [25] Permeation Stability Therapeutic effect [26]

The following paragraphs will briefly describe the main types of NPs that have been developed.

Stabilized fluorocarbon microbubbles have been extensively studied as US contrast agents since they have optimal bioavailability as well as proper size management. They are not metabolized and are excreted through the respiratory system as the patient exhales [14]. In the last few decades, many pre-clinical studies have explored the possibility of using these in ablation and drug delivery applications, especially in cancer. Most preclinical studies loaded chemotherapy drugs, often doxorubicin (DOX), in the microbubble shell and directed drug release by bursting the bubbles in the precise tumor area with focused ultrasound [27]. The precision of delivery and reduction of side effects were promising, but the amount of drug that could be loaded into the microbubbles was often insufficient [28]. Geers et al. tried to overcome this issue by attaching secondary carriers to the shell and demonstrated that 600 to 1300 DOX-loaded liposomes could be attached to a single microbubble, significantly increasing the loading capacity [25]. Despite having encouraging results, these studies highlighted some intrinsic limitations of microbubbles, mainly due to their size, resulting in too short shelf-lives and in vivo circulating time and half-lives [18].

Phase-change fluorocarbon nanodroplets are nanobubbles (5 to 500 nm), developed with the aim of overcoming some of the problems that emerged with microbubbles [24]. They are made of condensed fluid – phase-change emulsion – droplets stabilized by an amphiphilic shell. Usually, the core is fluorocarbon and the shell is lipidic or polymeric [29]. They are advantageous compared to microbubbles in many aspects. First, once the liquid core of the nanodroplets is exposed to FUS pulses, it vaporizes, creating microbubbles, which then lead to cavitation with better lateral focusing and fewer side effects outside the targeted area [27]. Furthermore, the liquid core of nanodroplets is more stable than the gaseous one of microbubbles, which allows them to be smaller in size, with longer shelf-lives and in vivo circulating time and half-lives [18].

Thermo-responsive materials

Among stimuli-responsive materials, those triggered by temperature changes are of particular interest for FUS.

Temperature-sensitive liposomes (TSLs) are made of a spherical lipid bilayer with a hydrophilic core. Hydrophilic active pharmaceutical ingredients (APIs) are dissolved in the core, while hydrophobic or amphiphilic APIs are directly encapsulated in the shell [30], though the latter are not as efficient with respect to retaining the drug and can cause systemic toxicity [26]. As demonstrated by a variety of preclinical studies, TSLs in combination with mild HT (41–45°C) can result in increased concentration, distribution, and therapeutic efficacy of a drug, due to the localized release and the augmented perfusion and vascular permeability of the targeted area [31] [32]. This category of NPs includes the FDA-approved formulation ThermoDox (Celsion, Columbia, MD), with the first clinical application being in 2005 combined with radiofrequency ablation (RFA), which also functioned as the HT source. Two main clinical studies followed, namely HEAT (NCT00617981) and OPTIMA (NCT02112656). However, these unfortunately yielded suboptimal results, with the latter in particular being discontinued prior to completion due to insufficient evidence of increased benefit from the ThermoDox + RFA treatment, compared to RFA alone [33]. Subsequently, FUS rather than radiofrequency was explored as a method for inducing hyperthermia and for the delivery of liposomes. Preclinical studies showed the feasibility of combining TSL and FUS. For example, in a proof-of- concept study on tumor-bearing rats, a 3T-MRgHIFU system has been used to reach HT for 30 min, thus triggering the release of DOX and gadolinium contrast medium. The presence of the contrast medium allowed monitoring of the release and, therefore, of DOX. Although it has some limitations, this study showed how the combination of HT and TSLs resulted in higher concentrations (2 to 10 times depending on the tumor) of the encapsulated drugs [34]. However, the long exposure time needed in the preclinical studies poses a challenge with respect to use in the clinical setting where it would not be feasible in all treatments necessitating breath-hold to avoid movement and in all cases where lesions are near larger blood vessels that would transmit heat. In this setting in a preclinical study, positive, though not comparable, drug release was still obtained with 10 sonications lasting 30s instead of longer ones, suggesting the possibility of reducing the single exposure time, allowing for easier applicability in the clinical setting [35]. While preclinical studies are trying to optimize treatment feasibility, one notable phase I study, namely TARDOX on patients with liver metastases [36], showed how USgFUS could safely enhance drug concentrations in a clinical setting. However, what emerged from this study is a lack of correlation between drug concentration and mean temperature or thermal dose, probably due to the heterogenous nature of temperature distribution. This finding encourages the use of MRI guidance, which allows for real-time thermometry and greater visualization of the target, thereby better ensuring temperature coverage and safety of the treatment. Finally, the PanDox Study (NCT04852367) [37] on non-resectable pancreatic cancer and the i-Go Study (NCT03749850) [38] on stage IV breast cancer are currently ongoing phase I studies, combining ThermoDox with MRgHIFU technology.

Micelles are made of polymeric molecules which self-assemble in colloidal systems once they reach critical temperatures and/or concentrations. Usually, for drug delivery purposes they are designed with a hydrophobic core, hosting the API, and a hydrophilic shell, enhancing solubility in the physiological environment and preventing micelle self-aggregation. Micelles are quite versatile with respect to drug delivery as targeting can be obtained either by cross-linking a ligand (including antibodies or peptides) to the shell to enhance target recognition or by making them sensitive to different stimuli [24]. For instance, thermo-responsive micelles have been tested by Nelson et al. for doxorubicin delivery triggered by LIFU [39]. Finally, these micelles could be engineered to be responsive both to mechanical and thermal FUS stimulation [24].

Magnetic nanocarriers

On the cutting edge of research, superparamagnetic iron oxide (SPIO) contrast agents have been investigated as drug localizers with the aim of triggering release specifically in the targeted area. Two studies have proven the efficacy and biocompatibility of magneto-responsive drug loaded NPs. Vítková et. al tested the magnetic, rheological, and biocompatibility properties of magneto-responsive soft hydrogels and suggested their usage in magnetic hyperthermia-triggered drug delivery [40]. Mallick et al. explored the potential of doxorubicin-loaded micro-sized magnetic NPs in anticancer therapy [41]. Another study investigated the influence of size and shape on the elicited effect and discovered how spherical NPs were linked to lesser cytotoxicity and were able to significantly control tumor growth in vivo in mice [42]. Finally, a recent study by Ren et al. designed and tested different gene-carrying nanobubbles whose delivery was mediated by LIFU impulses for the treatment of osteosarcoma [43]. Another promising result was achieved in mice treated with a particular NP designed as a pegylated nanobubble with SPIO in order to control not only the time of release via US bubble destruction but also the location in the targeted area [43]. Although there is still a paucity of published evidence, this extremely novel approach opens up the intriguing possibility of either localizing (with MRI) or directing (with a suitable magnetic field) the NPs and then triggering release via US microbubble destruction and warrants further investigation.

Musculoskeletal applications

Bone can be affected by a variety of disorders and pathologies. Due to its physiology, bone is a challenging target for drug therapies as it is relatively avascular and is therefore difficult to reach after systemic administration, and, once damaged, it is full of empty spaces, resulting in the unwanted ability to harbor pathogenic bacteria [44].

Cancer

There are several ongoing clinical trials assessing the use of FUS in pain palliation and thermal ablation in different oncologic populations. Its synergistic action with chemotherapy drug release is a topic of current interest, as the reversible increase in blood vessel and membrane permeability induced by sonoporation enhances drug release in the targeted area, thereby increasing its therapeutic efficacy [45] [46]. For example, in a retrospective study, Zhang et al. showed how in a cohort of 185 patients with abdominal lymph node metastasis, those who underwent HIFU for palliative treatment in association with chemotherapy overall showed better pain relief and greater survival rates [47].

Osteosarcomas, chondrosarcomas, and soft tissue sarcomas

Several preclinical studies have explored the potential of attacking tumors simultaneously with ablation and chemotherapy [7] [48] [49]. Regarding musculoskeletal cancers, in particular osteosarcomas and chondrosarcomas, two interesting studies were recently published. The first one investigated the use of HIFU-mediated sonodynamic therapy on spontaneous canine cancer. The investigators delivered an anticancer micelle loaded with epirubicin as a sonosensitizer. The average tumor volume shrinkage was 15%, with a significant reduction in symptomatology and an elongation of life expectancy (mean = 11 months). Although the study included only four dogs, the results were so promising that they triggered further preclinical investigation, with the hope of a prompt transfer of such procedures into clinical practice [50]. The second study is an ongoing Phase I clinical trial (NCT02536183) on osteosarcomas testing the combined use of lyso-thermosensitive liposomal doxorubicin and MRgHIFU in pediatric refractory solid tumors, in particular Ewing’s sarcoma and osteosarcomas [51]. Finally, Sebeke et al. assessed the feasibility of a clinical translation of DOX-TSL in association with MRgHIFU treatment, testing TSL infusion, adverse immune reaction rates, and prolonged hyperthermia effects in a healthy pig model [52].

Bone infections

Once damaged, bones become rich in necrotic tissue and particularly sequestra, which create void spaces where bacteria can grow and are almost completely unreachable by conventional drugs [44]. Furthermore, in periprosthetic infections, bacteria biofilms play a crucial role in the failure of antimicrobial therapies [53] ([Fig. 3] [54]). Biofilm antimicrobial resistance is believed to derive from different mechanisms, including matrix formation with reduced clearance by the immune system.

Fig. 3 Biofilm formation. Biofilms form in four main stages: a) pathogens reach the target tissue b) attachment to a surface (e.g., the tissues surrounding a prosthesis), c) proliferation with matrix formation d) biofilm formation, e) and finally dispersal, which may lead to the dissemination of a biofilm-associated infection[55].

Periprosthetic and fracture-related infections

Metallic implants, such as screws and joint prostheses, are widely used in orthopedics and are linked with an overall infection rate of 1–2% [55]. The most common infections are caused by Pseudomonas aeruginosa and Staphylococcus aureus, which are highly resistant bacteria, usually found as biofilms in wounds [56]. Due to the lack of effective antimicrobial treatments, re-implantation after cleansing and debridement of the infected zone is usually the only therapeutic option but is associated with risks of secondary infections, re-infections from the same pathogen, and surgical or anesthesiologic complications [55]. This kind of approach is often used even in the case of fracture-related infections but with unsatisfactory results [57]. It is desirable to use local antibiotic therapy, when possible, in order to reduce systemic side effects and increase the drug concentration at infected sites. However, further development of drug delivery systems is still needed to overcome some of the limitations associated with topical therapies, such as hypersensitivity reactions, dermatitis, and antimicrobial resistance [58]. A preclinical study by Wardlow et al. demonstrated how low-TSLs loaded with ciprofloxacin triggered by MR-HIFU can effectively release the loaded drug both in vitro and in vivo. Furthermore, they showed how prolonged treatment at 42°C can actually disrupt both the biofilm matrix and the bacterial membrane of Staphylococcus aureus in murine models [59]. Another pre-clinical study on Pseudomonas aeruginosa biofilms highlighted how HIFU could reduce the biomass and erode the biofilm. Unfortunately, this effect was counteracted by a resilient response from the bacteria biofilm that developed partial antibiotic resistance, making the treatment only moderately effective. As a result, the investigators underlined the importance of considering the physical and biological action on the pathogen simultaneously [60].

Osteomyelitis

Osteomyelitis is characterized by a profound inflammatory state of bones usually caused by an invasive infection from a contiguous source or via hematogenous spread [61]. Even in this case, antimicrobial treatment is not necessarily effective and clinical management remains complicated, as the most common pathogen is Staphylococcus aureus [62]. A recent preclinical study investigated the use of low-TSLs loaded with ciprofloxacin combined with HIFU in a rat model infected with methicillin-resistant Staphylococcus aureus (MRSA). Results showed how the combined effect was able to significantly reduce the pathogen population compared to HIFU or ciprofloxacin treatments alone [63].

Our search highlighted a lack of clinical evidence on the use of MR-guided FUS for the delivery of antimicrobials in bone infections. However, because of the huge threat posed by antibiotic resistance as well as the need to develop novel and resolutive therapeutic options for these pathologies, future studies on the topic would be of paramount importance.

Arthritis

Arthritis is a chronic disease characterized by severe joint pain that can lead to loss of function if not properly treated [64]. While rheumatoid arthritis (RA), lupus arthritis, and gout have long been known as being inflammatory-based and triggered by an over-active immune system, recent evidence suggests a similar pathway also for osteoarthritis (OA) [65]. Current OA therapies aim at improving the symptomatology [66], but to effectively cure the pathology, the available evidence shows the need to target the immune system. This could be achieved by using nanocarriers to induce autoimmune tolerance or to trigger the production of regulatory-like T cells, involved in the pathogenic pathway [67]. HIFU-triggered nanomaterials are of particular interest if one considers the intrinsic rise in temperature (as a consequence of the inflammatory state) in the affected tissues [68]. An in vitro study by Nieminen et al. demonstrated how it is possible to safely and effectively deliver small molecules (320 Da) into the articular cartilage by increasing its permeability via HIFU sonication [69]. While addressing the limitation of an in vitro study and the relatively small size of the delivered molecule, this study helped by suggesting new ways to achieve targeted delivery in a pathology where the lack of effective treatment is still a concern. In the last decade, some studies successfully developed nanocarriers for arthritis treatment, but unfortunately clinical translation has not yet been achieved as most of the materials that are used are non-biodegradable [70]. It should be noted that a preclinical study on murine knees showed that thermo-responsive, self-aggregating, and biodegradable elastin-like polypeptides can form an intra-articular depot able to slowly release the drug, suggesting the possibility of further exploring this material [71]. Concerning RA, diclofenac was successfully delivered to mice joints by exploiting US-MB delivery and consequently increased tissue permeability [72]. At present, taking advantage of the increased tissue permeability caused by FUS appears to be one of the most promising paths to follow in the treatment of arthritis.

Challenges and future directions

The last few decades have seen extensive research activity regarding FUS-triggered exogenous drug delivery with significant technological progress and promising preclinical results ([Fig. 4]). Furthermore, some exploratory clinical trials have recently been initiated, mainly in the neurologic and oncologic fields, highlighting some of the exciting possibilities of such techniques. In addition to cancer treatment, bone infection treatment has emerged as another important and promising topic of interest. Various studies have demonstrated that synergistic use of FUS hyperthermia and antimicrobial drugs could allow simultaneous targeting of different bacterial pathogenic pathways and disrupt the almost therapeutically unreachable biofilm layer. In general, the main limitations that need to be overcome to achieve clinical application relate to the carriers in which the drugs are loaded. Overall, the most promising type, with some examples already being clinically approved, are liposomes [73]. However, in order for them to be more widely clinically feasible and cost-effective, these nanoparticles need to be more stable, have greater bioavailability, and be less expensive to produce and test [74]. Currently, most of these therapies are too costly and complicated with regard to both synthesis and administration [25] [75]. For example, an analysis regarding nanosized and minimal-carrier drug delivery systems by Etter et al. highlighted how it is of paramount importance to increase the drug loading in order for these technologies to be more cost-effective [76]. Another issue is the difficult translation from animal models to humans, as the response of different organisms makes it difficult to properly assess toxicity and efficacy [20] [75]. Therefore, along with more safety and efficacy trials, we believe that more progress in pharmaceutical technology is needed for FUS-mediated drug delivery systems to gain proper clinical and industrial interest.

Fig. 4 Summary of the different studies included in the review categorized according to NPs, along with their delivery technologies, target, and evidence level.

Conclusion

The present narrative review makes it possible to draw conclusions. First, the safety and efficacy of FUS and FUS-HT in drug delivery have been demonstrated by a variety of preclinical studies. Most evidently, FUS-mediated drug delivery may be an elegant method for treating both primary and secondary bone cancer, but it may also be a promising tool in other challenging therapeutic areas like bone infections. Furthermore, although there is still a paucity of original research on the treatment of arthritis with FUS-mediated drug delivery, the initial evidence suggests an interesting therapeutic possibility to address the pathology. The dual ability of US to trigger drug delivery, via microbubble destruction or hyperthermia, and to increase tissue permeability appears to be particularly interesting when it comes to the treatment of difficult targets, like bone and cartilage. When the ability of MRI to monitor temperature changes and to localize drug accumulation in vivo is also considered, then the advantages of continuing to research this field become increasingly evident ([Fig. 5]). This article highlights the need to further investigate this field, especially at the clinical level, with the ultimate aim of reducing antimicrobial resistance and discovering better therapies to improve patient healthcare and quality of life in a more personalized and efficient manner.

Fig. 5 Visual summary of MSK FUS-mediated drug delivery applications.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 07 February 2025

Accepted after revision: 20 November 2025

Article published online:
30 January 2026