Increasing evidence suggests that an exogenous electromagnetic field might be involved in many biologic processes which are of great importance for therapeutic interventions. Pulsed electromagnetic fields (PEMFs) are known to be a noninvasive, safe and effective therapy agent without apparent side effects. Numerous studies have shown that PEMFs possess the potential to become a stand-alone or adjunctive treatment modality for treating musculoskeletal disorders. However, several issues remain unresolved. Prior to their widely clinical application, further researches from well-designed, high-quality studies are still required to standardize the treatment parameters and derive the optimal protocol for health-care decision making. In this review, we aim to provide current evidence on the mechanism of action, clinical applications, and controversies of PEMFs in musculoskeletal disorders.

Background: Although lower temperature (< 45 °C) photothermal therapy (LPTT) have attracted enormous attention in cancer therapy, the therapeutic effect is still unsatisfying when applying LPTT alone. Therefore, combining with other therapies is urgently needed to improve the therapeutic effect of LPTT. Recently reported oxygen-irrelevant free radicals based thermodynamic therapy (TDT) exhibit promising potential for hypoxic tumor treatment. However, overexpression of glutathione (GSH) in cancer cells would potently scavenge the free radicals before their arrival to the specific site and dramatically diminish the therapeutic efficacy. Methods and results: In this work, a core–shell nanoplatform with an appropriate size composed of arginine–glycine–aspartate (RGD) functioned polydopamine (PDA) as a shell and a triphenylphosphonium (TPP) modified hollow mesoporous manganese dioxide (H-mMnO₂) as a core was designed and fabricated for the first time. This nanostructure endows a size-controllable hollow cavity mMnO₂ and thickness-tunable PDA layers, which effectively prevented the pre-matured release of encapsulated azo initiator 2,2′-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIBI) and revealed pH/NIR dual-responsive release performance. With the mitochondria-targeting ability of TPP, the smart nanocomposites (AIBI@H-mMnO₂-TPP@PDA-RGD, AHTPR) could efficiently induce mitochondrial associated apoptosis in cancer cells at relatively low temperatures (< 45 °C) via selectively releasing oxygen-irrelevant free radicals in mitochondria and facilitating the depletion of intracellular GSH, exhibiting the advantages of mitochondria-targeted LPTT/TDT. More importantly, remarkable inhibition of tumor growth was observed in a subcutaneous xenograft model of osteosarcoma (OS) with negligible side effects. Conclusions: The synergistic therapy efficacy was confirmed by effectively inducing cancer cell death in vitro and completely eradicating the tumors in vivo. Additionally, the excellent biosafety and biocompatibility of the nanoplatforms were confirmed both in vitro and in vivo. Taken together, the current study provides a novel paradigm toward oxygen-independent free-radical-based cancer therapy, especially for the treatment of hypoxic solid tumors. Graphical

Background: Although systemic chemotherapy is a standard approach for osteosarcoma (OS) treatment, its efficacy is limited by the inherent or acquired resistance to apoptosis of tumor cells. Ferroptosis is considered as an effective strategy capable of stimulating alternative pathways of cancer cell demise. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy. Methods and Results: A novel nanovehicle composed of arginine-glycine-aspartate (RGD) modified mesoporous silica-coated iron oxide loading Fin56 was rationally prepared (FSR-Fin56). With the RGD-mediated targeting affinity, FSR-Fin56 could achieve selective accumulation and accurate delivery of cargos into cancer cells. Upon exposure to NIR light, the nanovehicle could generate localized hyperthermia and disintegrate to liberate the therapeutic payload. The released Fin56 triggered the degradation of GPX4, while Fe³⁺ depleted the intracellular GSH pool, producing Fe²⁺ as a Fenton agent. The local rise in temperature, in conjunction with Fe²⁺-mediated Fenton reaction, led to a rapid and significant accumulation of ROS, culminating in LPOs and ferroptotic death. The outstanding therapeutic efficacy and safety of the nanovehicle were validated both in vitro and in vivo. Conclusion: The Fin56-loaded FSR nanovehicle could effectively disturb the redox balance in cancer cells. Coupled with NIR laser irradiation, the cooperative CDT and PTT achieved a boosted ferroptosis-inducing therapy. Taken together, this study offers a compelling strategy for cancer treatment, particularly for ferroptosis-sensitive tumors like osteosarcoma.

Background: Despite advances of surgery and neoadjuvant chemotherapy during the past few decades, the therapeutic efficacy of current therapeutic protocol for osteosarcoma (OS) is still seriously compromised by multi-drug resistance and severe side effects. Amplification of intracellular oxidative stress is considered as an effective strategy to induce cancer cell death. The purpose of this study was to develop a novel strategy that can amplify the intracellular oxidative stress for synergistic cascade cancer therapy. Methods and results: A novel nanocomposite, composed of folic acid (FA) modified mesoporous silica–coated gold nanostar (GNS@MSNs-FA) and traditional Chinese medicine lycorine (Ly), was rationally designed and developed. Under near-infrared (NIR) irradiation, the obtained GNS@MSNs-FA/Ly could promote a high level of ROS production via inducing mitochondrial dysfunction and potent endoplasmic reticulum (ER) stress. Moreover, glutathione (GSH) depletion during ER stress could reduce ROS scavenging and further enable efficient amplification of intracellular oxidative stress. Both in vitro and in vivo studies demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation exhibited excellent antitumor efficacy without noticeable toxicity in MNNG/HOS tumor-bearing mice. Conclusion: All these results demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation could dramatically amplify the intra-tumoral oxidative stress, exhibiting excellent antitumor ability without obvious systemic toxicity. Taken together, this promising strategy provides a new avenue for the effective cancer synergetic therapy and future clinical translation.

Chemodynamic therapy (CDT) is an effective anti-tumor method, while CDT alone cannot achieve a good therapeutic effect. Moreover, the overexpression of glutathione (GSH) in tumor cells dramatically limits the efficiency of CDT. Here, we proposed a hydrogel co-loading SO₂ prodrug and FeGA nanoparticles (NPs) for enhancing CDT by photothermal-triggered SO₂ gas therapy (FBH) system by mixing benzothiazolyl sulfonates (BTS) and FeGA NPs in a certain ratio and encapsulating them in a heat-sensitive hydrogel. FeGA NPs could accelerate the release of Fe²⁺ under acidic conditions and light, and combine with excess H₂O₂ in the tumor for chemokinetic treatment. BTS, as a water-soluble prodrug of SO₂, can accurately control the release of SO₂ gas by virtue of the excellent photothermal conversion ability of FeGA NPs and the acidic pH value of tumor site. SO₂ can not only induce cell apoptosis, but also consume excess GSH in cancer cells and increase the content of reactive oxygen species, which seriously destroyed the redox balance in cancer cells and further promotes the therapeutic effect of Fenton reaction. The intelligent FBH system provided a new approach for the synergistic treatment of CDT and SO₂ gas, which demonstrated good anticancer effects both in vivo and in vitro.