Phototherapy, which includes two categories of photothermal therapy (PTT) and PDT, is a non-invasive procedure approved by the FDA. PDT comprises three main components: Photosensitizer, oxygen, and light (Goh et al., 2010). Efficient singlet oxygen is produced when a photosensitizer reacts with oxygen molecules under a specific wavelength of laser light. These singlet oxygens damage tumor cells and arteries by inducing cells to apoptosis, necrosis, and activation of immune responses. But with the salient advantages, you must also know some disadvantages (Xavierselvan et al., 2022).

When PS absorbs photons in the light, it changes from the base state to the transient state. This unstable state chooses one of two paths. It returns from the singlet state to the ground state by emitting fluorescence or energy loss. The second path changes from the singlet state to the long-lived triplet state through an intersection within the system (Hu et al., 2019). This triplet mode transfers energy to oxygen molecules through two mechanisms. Radical species are constructed by repositioning hydrogen or electrons when PS responds with organic molecules. Finally, radical species can react with oxygen to produce reactive oxygen species (ROS). In the second mechanism, the PSs in the excited state transfer energy directly to the oxygen molecules and lead to the production of activated singlet oxygen. These ROS oxidize subcellular organelles and destroy blood vessels (Wang et al., 2020). It eventually leads to light-induced cell death. In the PDT technique, the lifespan of singlet oxygen in PFCs is more extended than the cellular environment and water, which leads to the long-term effects of this technique. Radiotherapy (RT) uses ionizing radiation (X-ray, or γray) to generate free radicals, which damage DNA directly and indirectly to other cellular elements to induce DNA impairment and induce cancer cell death. Under hypoxia, these injuries heal immediately. This method is used in clinics to treat cancer. A little part of the energy of this radiation is fascinated by tumor cells. Most of this energy harms normal tissues; this method is non-specific. But oxygen molecules during radiotherapy forms radical peroxide that is more destructive and problematic, thus making it impossible for cell repair and DNA damage to stabilize. Cell damage by ionizing radiation depends to a large extent on the oxygen level of the cells. The environment around the tumor is hypoxic compared to healthy cells, so it is necessary to optimize it to increase the efficiency of this method. Liquid PFCs are widely used to optimize this treatment (Song et al., 2017). Table 2 lists several NPs combined with PFC to overcome the hypoxic conditions used in combination with photodynamic therapy and radiotherapy.

Photodynamic therapy, which is one of the new methods in the treatment of cancer, whose anticancer effect is related to reactive oxygen species and singlet oxygen produced by oxygen in the photodynamic reaction. However, PDT turns off the vascular and consumes oxygen, In this condition, oxygen is less and hypoxia is intensified. After attaining superior anti-tumor therapy tracing the development of an effective approach to dominate a hypoxic tumor surrounding is highly desirable. Compared to other solvents, perfluorocarbons increase the half-life of singlet ¹O₂ by 10⁵ folds, so they are a very suitable carrier for oxygenation and overcoming hypoxic conditions (Fang et al., 2021).

Cell therapy approach used in treating various diseases, including cardiovascular disease, ischemia, type 1 diabetes, and cancer. Different stem cells and immunity are used for this purpose, but its tracing is essential to evaluate the function and position of the transplanted cell. Optic, ultrasound, MRI, CT, PET, and SPECT imaging modalities detect transplanted cells (Stanton et al., 2016). Different contrast agents are required depending on the technique.

PFCs are used in MRI and Ultra Sound imaging modalities. In the previous section, the importance of PFCs in imaging was discussed. Tracking is performed using the techniques discussed in the precautious section. But in this section, the different tissues to which the cell is attached and the role of PFCs as oxygen carriers are given in Table 3. These cells detect tumor antigens and have the ability to migrate to tissue and eventually penetrate tumor tissue. In an in vitro study, Gonzales et al. Labeled splenocyte and Ovalbumin T-cells with PFC and then examined them by FMRS/MRI. In an in vivo study, Gonzales and colleagues labeled splenocyte and ovalbumin T-cells in the liver, spleen, and lung with PFC and then examined them by FMRS/MRI. Finally, they concluded indivisible cells labeled with 19F are promising for FMRS/MRI-modality tracking. Therefore, labeling cells with PFC compounds such as perfluoropolyether (PFPE) is a promising way to monitor the treatment of cancer cells. FDA-approved PFC compounds used to label and track cells by FMRI are Cell Sense and V-Sense (Wu et al., 2020).

Thrombus formation is critical in numerous cardiovascular disorders such as ischemic stroke, myocardial infarction, deep venous thrombosis, and pulmonary embolism, which are meaningful causes of morbidity and mortality worldwide (Stein et al., 2005; Taghizadeh et al., 2020). Also, Thrombus formation is the prime concern for using blood-contacting medical devices (Mauri et al., 2007; Mauri et al., 2014; Grover and Mackman, 2019; Virani et al., 2020). Percutaneous coronary intervention (PCI) and fibrinolysis with various anticoagulants and antiplatelet agents are the standard therapeutic procedures to prevent further clot progression field (Chattopadhyay et al., 2011; Olaf and Cooney, 2017). The restorative examples have limitations, including an almost short time window consistent with fierce regimens, thrombus formation still proceeding, and severe bleeding from using the systemically active anticoagulants (Osório, 2010; Robert, 2010; Siegel et al., 2022). Therefore, developing safer anticoagulants and a non-invasive treatment method is an ongoing pharmaceutical chase for managing thrombotic events in CVD Table 4 (Tran et al., 2007; Chen et al., 2021a; Wu et al., 2021). In this interest, PFC NPs, microbubbles composed of PFC combination with standard External low-frequency ultrasound (USD), define a medium technology with adjustable molecular imaging and provincial drug delivery in thrombosis events (Ravis et al., 1991; Flaim, 1994; Leese et al., 2000; Jacoby et al., 2014; Roberts et al., 2020; Manners et al., 2022). Myerson et al. (2010); Myerson et al. (2011) synthesized PPACK (Phe [D]-Pro-Arg-Chloromethylketone) and fastened these structures to the surface of PFC-core nanoparticle with the covalent bonds. These structures showed that the PPACK PFC nanoparticle could be an effective anticoagulant and prevent thrombosis, although the PPACK has not had these features alone. An increase in the number of PPACK ligands resulted in the maintenance of anticoagulants effects at the site of thrombosis and inhibition of activated thrombin event and inflammation (Figure 3). Bouvain and colleagues generate a non-invasive approach for explicit mapping of neutrophil dynamics by 19F-based MRI probes, using PFCs. In-vivo data showed this technique let to recognize undercover origins of inflammation in patients and also to separate cardiovascular disease circumstances on the point of extreme aggravation due to enriched neutrophil infiltration or activation (Bouvain et al., 2023). Liposomal bubbles (bubble liposome, BL) constructed of PFC gas and nano-sized liposomes covered by RGD sequence peptides on their exterior shell. These liposomal bubbles can connect to the glycoprotein IIb/IIIa complex. Mentioned complex duty is activating platelets which can improve the visualizing and accurate detection of exciting thrombus by conventional diagnostic ultrasound probes for thrombus imaging and disruption in vitro and in vivo (Hagisawa et al., 2013). Hagisawa et al. research indicated the fact that the reduction in speed of the clot with targeted liposomal bubbles was significantly more elevated than with non-targeted. Also, it proved that High-intensity USD orientation with targeted BL can acquire arterial recanalization in 90% of arteries, and the time to perfusion was quicker than the results for rt-PA therapy. Blood coagulation in Medical devices is one of the most challenging problems in designing these devices; the best approach for preventing coagulation is to use tethered liquid PFC (TLP) coating on the surface of instruments. The TLP bilayer coating decreases the adhesion of blood and prevents thrombus formation. Roberts et al. (2020) used TLP-coated (Tethered Liquid PFC) ECLS circuitry and immobilized-heparin on the surface; the coating was established for 6 h of circulation in swine and using no systemic heparin. The result is that TLP enables heparin-free ECLS for 6 h not to alter the membrane’s critical coagulation and does not affect gas exchange efficiency versus the clinical standard—immobilized heparin. Another challenging crisis is thrombus formation by conventional MRI and 1H MR angiography. These techniques may have an insignificant impact on blood flow. Biologically inert PFC nanoemulsions are used as 19F MRI, a unique technique for molecular imaging (Spuentrup et al., 2005a; Spuentrup et al., 2005b; Stoll et al., 2012; Guo et al., 2021). Temme et al. (2015) worked on new generating approaches in nan invasive for diagnosis with 1H/19F MRI acute deep venous thrombosis and pulmonary thromboembolic design targeted PFCs with sterol-based post-insertion technique (SPIT). This structure generates α2-antiplasmin–labeled PFCs (α2AP-PFCs) and allows the qualification of accomplished PFCs under favorable circumstances that sustain the functionality of labile ligands.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory condition categorized as an autoimmune disease affecting approximately 1% of the global population (Giannini et al., 2020; Jahangir et al., 2022). RA is categorized as an autoimmune disease influencing approximately 1% of the global population. Disease manifestations are ongoing inflammation of synovial tissues, leading to articular cartilage and bone breakdown in the afflicted joints, and, in the long term, consequences are a significant functioning disability and actual death (Kourilovitch et al., 2014). The leading cause of this disease has not yet been defined. First, inflammation starts in synovium because of population increases of fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes (MLS), and hyperplasia in synovial tissue is showed. In the continuation of these changes, the synovial cells secreting metalloproteases (MMPs) and TNF-a trigger the growth of osteoclasts, which cause bone bruises (McInnes and Schett, 2007). All these events lead to chronic inflammation in RA by swelling and accumulation of recalling other inflammatory cells, such as macrophages and lymphocytes, and fibroblasts are activated (McInnes and O’Dell, 2010). Other factors that are involved in the inflammatory progress and irreversible damage to the cartilage in RA are TNF-a and IL-17; these factors have synergistic effects in boosting the production of IL-1, IL-6, and IL-8 and granulocyte territory stimulating factor (G-CSF) MMPs (McInnes and O’Dell, 2010; Chen et al., 2021b). Many aspects are involved in the onset of RA; for example, genetically predisposed people can suffer from this disease under the influence of environmental aspects such as bacterial or viral infection (Perricone et al., 2019).

Further environmental risk factors for RA include smoking, alcohol use, birth weight, breastfeeding, socioeconomic status, and ethnicity (Viatte et al., 2013; Paulissen et al., 2015; Baker et al., 2020; Ishikawa and Terao, 2020). Numerous imaging methods, for instance, MRI and computed tomography, diagnose RA patients. Early detection and prevention of further damage to the cartilage tissue is the most critical aspect of the treatment of RA; the main challenge in imaging procedures is the accurate diagnosis and quantified depth of damage in this disease to provide a practical guide to determine the exact dose of drug therapy (Wu et al., 2020) In line with the combination of imaging methods to achieve a good result researchers combined near-infrared (Sen Gupta, 2017) with 19f MRI used tagged NPs constructed from PLGA-PEG-Folate (Folate-NP), loaded with PFOB and indocyanine green (ICG) (Zhou et al., 2012; Vu-Quang et al., 2019). A common choice for RA patients to control symptoms establishes convergence with analgesics such as NSAIDs; combined regimens are usually preferred for achieving the best results and prolonged use (Svanström et al., 2018). Other choices in the remedy of RA can be mentioned as glucocorticoids (GCs), especially at the beginning of the treatment; this category of drugs in combination with co-therapy with other DMARDs is preferred. GCs show fast and effective outcomes, and because of the lower cost compared to other DMARDs, they are widespread. The main concern of GCs is high side effects in the long term, including an increased risk of cardiovascular disease, osteoporosis, infections, and altered glucose metabolism, which are usually not included in the patient’s medication regimen for a long time (Hardy and Cooper, 2018; Wu et al., 2021).

Methotrexate (MTX) is the standard DMARD treatment for RA. The mechanism of MTX is the inhibition of dihydrofolate reductase (DHFR). More contemporary methods of RA treatment, such as cytokine antagonists (TNF, IL-1, and IL-6 inhibitors or receptor antagonists), B-cell-depleting drugs, and T-cell disbursement modulators, can be mentioned. The most effective approach so far is particularly TNF inhibitors with MTX, which obtained responses from 60% to 70% of RA patients in the early stages of the disease. Nevertheless, high costs, the chance of spreading complications, and the loss or defeat to hold reaction over time are major problems in these approaches (Hayashi et al., 2020; Maciejewski et al., 2021).

As mentioned, handling the side effects of drugs is an important issue due to the chronicity of RA disease and compelling the patient to use therapy for a prolonged. The resolution is encapsulating the bioactive substances and modifying NPs for targeting the desired tissue, which leads to a reduction in the dosage and, ultimately, a reduction in side effects (Hoes et al., 2010) (Ye et al., 2008).

PFC nanodroplets with low boiling temperatures are now widely employed in ultrasonic medication delivery. Besides PFC biocompatibility and biodegradability, surface functionalizing with molecules such as PEG can boost the circulation period. The medication enclosed in the droplets can be given passively through increased permeability and retention (EPR) (Astafyeva et al., 2015). Zhu et al. (2019) synthesized folate and PEG-modified PFP-based nanodroplets loaded with Dexamethasone. For in-vivo testing, collagen-induced arthritis (CIA) SD rat model was developed. The in vitro drug release of “nanobombs” and contrast-enhanced US imaging were comprehensively studied. Targeting and cell viability of triggered macrophages were then tested, as shown in (Figure 4). The US expands the passive target through the EPR effect and discharges more drugs by eliminating the nanodroplets and the result indicated extraordinary inhibition of synovitis and joint collapse by declining the level of pro-inflammatory cytokines, acting as an effective targeted drug for RA therapy (Zhang et al., 2018). Anti-angiogenic fumagillin, a mycotoxin produced by Aspergillus fumagatus, inhibits the MMP2; Zhou et al. (2009a) demonstrated that v3-targeted PFC NPs administered systemically accumulated to the inflamed joints and quashed inflammatory arthritis.

In another work, Zhou and colleagues revealed that in a mouse model of arthritis, a single dosage of fumagillin-PFC NPs was injected systemically and synergized with the customary DMARD MTX to give numerous anti-inflammatory advantages with an adequate safety profile (Zhou et al., 2010). Zhou et al. (2012) utilize a lipase-labile (Sn 2) fumagillin prodrug associated with a lipid surface-to-surface targeted delivery mechanism. Dissolved fumagillin comparative to the PFC core and lipid-gadolinium conjugates in vivo to ease drug delivery and early drug release and overcome the inherent photo-instability of fumagillin.

Tang et al. (2017) nanoscale PLGA drug delivery system encapsulated oxygen-saturated PFP and IC. Tang’s study examined the cytotoxic effects of OI-NP–mediated PSDT against FLSs in vitro. Data showed that the OI-NPs were a steady and efficient carrier for delivering oxygen and indocyanine green, and the NPs increased cellular absorption in MH7A cells. In addition, MH7A cells treated with PSDT indicated an increase in the appearance of intracellular ROS. Pretreatment with the ROS scavenger N-acetylcysteine reversed the OI-NP–mediated PSDT–induced cell survival decrease.

Muscular dystrophies are disorders that show symptoms of dystrophic pathologic characteristics on muscles. Dystrophinopathies affect 1 in 5,000 to 1 in 6,000 live male births worldwide. Clinically cause, progressive weakness and defeat of muscle mass, and substantial mutability exist in the genetic and biochemical points. All these aspects result in a commonness of muscular dysfunction and respiratory and cardiac compromise, and the eyes and central nervous system may be under effect, too. Cognitive impairment, learning difficulties, and behavioral problems were also demonstrated later (Dongsheng et al., 2021). The manifestations of muscular dystrophies can be different in further people; various factors, such as genetic differences, affect the time of onset and severity of disorder complications. Current treatment for muscular dystrophy mainly comprises controlling the symptoms and reducing the patient’s crises, such as using corticosteroids. Of course, treatments based on genetic modification are under research, which hopes to restore the lost function in these patients. However, picking the proper treatment is still a challenge in the Muscular dystrophies (Carter et al., 2018; Pennati et al., 2021).

PFCs NPs are expressed as drug delivery carriers for muscular dystrophy therapeutic substitutes. As an outcome, this approach can enable reducing some expected adverse effects, such as toxicity in the long term. The PFC particles limit drug uptake in normal tissues and can target the desired area in muscular dystrophies. Research has investigated insufficient autophagy in mdx mice (Duchenne muscular dystrophy model) treated using PFC NPs loaded with rapamycin. Structure induces growth in skeletal muscle strength over the extent of cardiac contractile rendition (Bibee et al., 2014).

There are numerous treatment options for solid tumor cancers. Among these techniques are pharmacological and chemotherapy approaches (Figure 5). Typically, cancer-specific drugs operate at the molecular level, specifically targeting a specific mutation. Nevertheless, it has been observed that cancer cells can evade the effects of drugs by completing a shortcut (Derakhshankhah et al., 2017). Therefore, chemotherapeutic methods are required to treat the disease. Radiotherapy and photodynamic therapy are included among the chemotherapy methods (Song et al., 2017; Hu et al., 2019). Although these strategies independently are not significantly adequate because part of the radiation is fascinated by healthy cells and the lack of oxygen in the tumor tissue, which is caused by inequality between oxygen supply and consumption due to the tumor’s rapid acceleration of the process of tumor growth. Tumors adapt their metabolism to oxygen-dependent microenvironments by activating hypoxia-inducing factors (HIF-1α) (Wang et al., 2020), which produce energy through an anaerobic process; hypoxic microenvironments regulate tumor growth and survival (Sun et al., 2020). Low oxygen levels in cells may be one of the primary causes of the uncontrolled growth of tumor cells in certain forms of cancer. Tissue oxygen deficiency is only a factor in the progression and development of cancerous masses; it is not the driving force. As the tumor’s oxygen level decreases, the tumor’s hypoxia worsens (Wang et al., 2020). Tumor cells express HIF-1 to survive in hypoxia. As a result of the genomic instability, altered tumor cell metabolism increased angiogenesis, and induced local immunosuppressive microenvironment caused by hypoxia, cancer cells become resistant to therapies. Two general strategies for overcoming tumor hypoxia are to deliver oxygen to the tumor site as a therapeutic agent and to take advantage of the unique environmental conditions that solid tumors have for targeted treatment.

Therefore, the oxygen concentration affects the efficacy of chemotherapy, photodynamic therapy, and radiotherapy. To have a toxic effect on cancer cells, this oxygen must exist in the singlet state. With the assistance of photodynamic therapy and radiotherapy, tissue oxygen can be converted to ROS. Oxygen-producing compounds and oxygen-carrying molecules can increase the oxygen concentration in tumor tissue to concentrate the effect of radiation on tumor tissue and overcome tissue hypoxia conditions, eventually leading to the death of more tumor cells. The article focuses on oxygen-carrying compounds, with PFCs being the most important. Zhou et al. (2019a). designed PFC and etoposide (EP) loaded porous hollow Fe₃O₄–based theranostic nano platform qualified of delivering oxygen to solid tumors to improve their vulnerability against EP. Outcomes showed that oxygen could be released at an average rate from the porous hollow magnetic Fe₃O₄ nanoparticles (PHMNPs) over a vast period, decreasing the hypoxia-induced EP resistance of tumor cells. Kim et al. created a drug delivery transport by exposure to near-infrared (NIR) light for drug release and tumor therapy. designed prepared based on a thin film method and utilizing Melanin, perfluorohexane (PFH), and 5-fluorouracil (5-FU)-loaded liposomes (melanin@PFH@5-FU-liposomes). The result indicated that tumor growth was virtually inhibited by the injection of melanin@PFH@5-FU-liposomes with laser irradiation (Kim and Lee, 2022).

Temperature and pH do not affect the oxygen-carrying capacity of PFCs. These PFC-based NPs have recently become famous for oxygenating tumors and enhancing the effects of anticancer treatments. PFC fluids such as PFTBA, PFP, PFH, PFOB, and others have been used as oxygen carriers for tumor hypoxia. These oxygen-carrying compounds are stabilized with lipids, polymers, and proteins because they are insoluble in water. With the immiscibility of oxygen in water, PFCs are emulsified with surfactants to serve as oxygen carriers. The surfactants Poloxamer F68 and Poloxamer 188 are two of these compounds.

PFC nanoemulsions are utilized in both liquid NPs and gas bubble forms. Nanoemulsions droplets, when evaporated, produce microbubbles and increase oxygen delivery to the tumor. In mice with pancreatic tumors, the partial pressure of tumor O₂ rises by up to 400% when small doses of F-Pentan Phase-Shift nanoemulsions (P-SNE) are used. However, this increase in oxygen pressure occurs under conditions that combine with carbogen or radiation; Under these conditions, the tumor volume decreases significantly (Krafft, 2020).

¹⁹FMRI method is very effective for quantitatively evaluating O₂ gas pressure around tumor tissues. Non-invasive methods produce O₂ gas pressure surrounding tumor tissue and recreate a guiding part in cancer treatment. With the assistance of the FMRI method, the pO₂ level of tumor tissue can be measured before and after oxygenation, in which case it is possible to control the tumor response appropriately to oxygenation. Because FMRI-relate because spin-network R1 relaxation rate is susceptible to pO₂. PFC emulsions can be injected intravenously or into the tumor and t, then the pO₂ of the tumor can be measured. Studies have indicated that tumor hypoxia is directly related to its size (Wu et al., 2020). Inspiring work done by Yang and colleagues designed an osimertinib-loaded perfluoro-15-crown-5-ether (AZD9291-PFCE) nanoemulsions, through intratracheal and intravenous delivery, synergizes with 119F MRI-guided low-intensity focused ultrasound (LIFU) for lung cancer therapy. Pulmonary delivery of AZD9291-PFCE nanoemulsions in orthotopic lung carcinoma models performs immediate diffusion of the nanoemulsions in lung tissues and tumors without side effects. Likewise, LIFU triggered drug release from the AZD9291-PFCE nanoemulsions and particularly boosts tumor vascular and tumor tissue permeability. The result showed validation of the treatment effect of AZD9291-PFCE nanoemulsions in resected human lung cancer tissues, confirming the translational prospect to enrich clinical outputs of the lung cancer therapy (Yang et al., 2022a).

If we examine perfluorocarbons in terms of safety in diagnosing and treating diseases, among various perfluorocarbon compounds, compounds such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) increase the risk of cardiovascular diseases compared to other PFC compounds. Compounds such as oxygenate and oxofluor were subjected to many safety tests, and although their results have not been published in scientific texts, they received a license for clinical use due to their safety (Spahn, 1999). The contrast agent Gd or iodate and PFC NPs can be utilized in molecular imaging. In a comparison between them, which was done to check the injury and function of kidney patients, the results indicated that NP PFCs do not have kidney toxicity and 24 h after consumption, the profile of them have good safety and no toxicity has been reported in human and animal samples (Chen et al., 2013). Table 4 include some clinical studies based on PFCs application in cancer treatment and diagnosis.