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Immune Repertoire and Advancements in Nanotherapeutics for the Impediment of Severe Steroid Resistant Asthma (SSR)

Abstract Severe steroid-resistant asthma (SSR) patients do not respond to the corticosteroid therapies due to the heterogeneity, and genome-wide variations. However, there are very limited reports pertinent to the molecular signaling underlying SSR and making pharmacologists, and formulation scientists to identify the effective therapeutic targets in order to produce novel therapies using novel drug delivery systems (NDDS). We have substantially searched literature for the peer-reviewed and published reports delineating the role of glucocorticoid-altered gene expression, and the mechanisms responsible for SSR asthma, and NDDS for treating SSR asthma using public databases PubMed, National Library of Medicine (NLM), google scholar, and medline. Subsequently, we described reports underlying the SSR pathophysiology through several immunological and inflammatory phenotypes. Furthermore, various therapeutic strategies and the role of signaling pathways such as mORC1-STAT3-FGFBP1, NLRP3 inflammasomes, miR-21/PI3K/HDAC2 axis, PI3K were delineated and these can be considered as the therapeutic targets for mitigating the pathophysiology of SSR asthma. Finally, the possibility of nanomedicine-based formulation and their applications in order to enhance the long term retention of several antioxidant and anti-asthmatic drug molecules as a significant therapeutic modality against SSR asthma was described vividly.


Introduction
Asthma is a chronic, inherited, heterogenous respiratory tract disorder exemplified by the presence of symptoms like cough, wheezing, stiffness of chest, respiratory tract inflammation, and remodeling. Global prevalence of asthma is increasing rapidly more than 350 million people worldwide. 1 A global action plan is taken for mitigating asthma and management of noncommunicable diseases and the UN-2030 agenda. 2 Despite the rising morbidity of asthma globally among both children and adults, there is no complete remedy for preventing this disease occurrence. This can be attributed to the heterogeneity nature of the disease. 3 Therapies against asthma can modulate heterogeneous clinical symptoms with variable responses. Corticosteroids are one of the significant therapies in treating mild to severe asthma; and they have been prescribed in early and long-term treatments as well. 4 Global initiative for asthma (GINA)-2021 in their strategy reported the usage of inhaled corticosteroids to the patients more than 6 years of age and adult asthmatic patients rather than compromising the treatment only the coming years. In this review, we have substantially described the molecular immune repertoire and underlying signaling pathways pertinent to SSR asthma, and anticipated therapeutic strategies formulated using the applications of nanomedicine as an alternative approach to produce good clinical outcomes through the targeted specific delivery of therapeutic molecules across secondary bronchi in asthma patients. This kind of delivery systems can enhance drug delivery, solubility, bioavailability, and pharmacokinetic profiles in order to minimize the acquired steroid resistance or to enhance the overall clinical outcomes in the asthma patients. [8][9][10][11]

Literature Search
We have extensively performed literature search in PubMed, National Library of Medicine (NLM), google scholar for the several published reports pertinent to the asthma patients who are with corticosteroid resistance, and the mechanisms underlying this resistance acquisition; furthermore, the literature pertinent to the various novel drug delivery systems including application of nanomedicine to treat this corticosteroid therapy resistance was also collected and deciphered vividly in this review.

Multiple Signaling Involved in Severe Steroid Resistant (SSR) Asthma
Exposure to higher ozone levels could induce the development of glucocorticoid insensitivity during asthma treatment. 12 In this study, the signaling mechanism pertinent to corticosteroid resistance in asthmatic patients with the increased exposure to ozone was delineated. 12 For instance, T2-low asthmatic condition was induced by the infiltration of neutrophils in asthma models by exposure to ovalbumin and ozone. Inflammatory and pro-inflammatory cytokines expression, lung resistance, etiology of lungs, modulation in the levels of GR and p-GR receptors, Nr3c1 mRNA, (STAT3), (SOCS3), and CXCL1 were ascertained for inducing corticosteroid resistance. Results of this study depicted respiratory tract inflammation due to the infiltration of neutrophils mediated by Th17 cells. A hormonal corticosteroid dexamethasone was used in the treatment of asthma conditions. A positive correlation in IL-6 and STAT3 levels and negative correlation between SOCS3 and STAT3 thus concluding that STAT3/IL-6 signaling pathway could be a significant factor for corticosteroid resistance. STAT3/IL-6 signaling pathway can be considered as a crucial therapeutic target to mitigate corticosteroid resistance. 12 Severe asthma is characterized by the induction of resistance to glucocorticoids. Severe asthma results from heterogenous immune phenotypes hindering the development of effective therapeutic targets. So, any novel therapeutic target for severe asthma requires in-depth understanding of cellular, molecular and signaling mechanisms underlying the phenomenon of corticosteroid resistance. Severe asthma is characterized by multiple factors like T-helper cell-2 low and T-helper cell-17 high, neutrophils infiltration causing inflammation of respiratory tract. Inflammatory cytokines like IL-17, IL-33 could be possible therapeutic targets. Sex and population type of asthmatic patient should also be taken into consideration during therapy. Most patients require combinatorial therapy due to the presence of different immune phenotypes. 7 For instance, a study conducted on asthmatic patients by dividing them into different groups like mixed asthmatics (eosinophilic/neutrophilic), paucigranulocytic, neutrophilic with usual FEV1, and neutrophilic with less FEV1 (asthmatics with smoking are included). Macrophage counts were estimated and observed a specific incline in the interferon regulatory factor 5 (IRF5+) levels and decline in the interferon regulatory factor 10 (IRF 10) levels. In addition, another signaling through purinergic receptors also plays a key role in the physiological processes in lungs for which ATP acts as a signaling messenger. A review discussed about possibility of purinergic receptors (P2RX1, P2RX4, P2RX7, P2RY1, P2RY11, and P2RY14) as therapeutic targets in asthma conditions. 13 Pentraxins receptors are soluble and exhibit a significant role in the pattern perception and modulation of innate immune responses. These receptors could be considered as biomarkers for various immune related diseases including respiratory disease like asthma, as they cause enhancement in the inflammatory response by interacting with various other proteins. 14 Therapies Against Corticosteroid Resistant Asthma Macrolides antibiotic which can be administered in combination with dexamethasone showed repression of lymphocytes. In addition, clarithromycin decreased inflammation and airway hyper-responsiveness by decreasing Th2 responses and TNF-α thereby leading to decrease in interleukin 17 responses that cause steroid-resistant asthma in mouse models. 15 Another study conducted on 232 asthmatic patients developed IgG antibodies to C. pneumonia when the patients were given treatment with roxithromycin for 6 weeks during the asthmatic condition. In a study on asthmatic children with confirmed chlamydia infection were treated with clathrithromycin showed typically decrease in the overall timespan of wheezing. Clarithromycin is also effective for the treatment of acute episodes of bronchospasm in children with a history of recurrent wheezing. 16 A randomized, double blind placebo controlled trial on 55 asthmatic patients reported a significant reduction in TNF-alpha, IL-5, and IL-12 levels in the respiratory tract. A study conducted on mouse models with steroid resistant asthma and H. influenzae infection induced by Th2 responses were controlled by clarithromycin treatment and the study concluded that H. influenzae infection shows synergistic effect on asthmatic patients. 15,17 In a study conducted on 45 steroid resistant asthmatic patients with clarithromycin treatment showed a significant mitigation in the IL-8, neutrophils, neutrophil elastase, matrix metalloproteinase-9 (MMP-9) concentrations and improved quality of life in asthmatic patients. 18 A study conducted on 420 patients concluded that azithromycin can be used as an adjunct therapy to treat steroid resistant asthma and enhanced quality of life in asthmatic subjects by decreasing symptoms. Hence, the nanoformulation composed of clarithromycin or combinatorial regimen of clarithromycin with other FDAapproved anti-asthmatic drugs may enhance the overall therapeutic window and bioavailability of the therapeutic molecules across the airways.

Targeting HDAC2 Axis and SSR Asthma
To reverse steroid resistance in SSR asthma after the glucocorticoids administration, it is crucial to develop therapies targeting the signaling molecules that stimulate or suppress the glucocorticoids activity; For instance, HDAC enzyme that deacetylates histone proteins and suppresses proinflammatory cytokines production. Glucocorticoid receptor mediated activity is enhanced by the steroid intake against asthma consequently suppress the proinflammatory gene expression by recruiting HDAC2 ( Figure 1); therefore, any decline in the HDAC2 could induce a higher inflammatory cytokine production linked to a significant role of HDAC2 in the acquisition of steroid resistance in bronchial asthma patients, [26][27][28][29][30] therefore, targeting this HDAC2 axis may be a crucial strategy to mitigate the pathophysiology of SSR.

Targeting phosphoinositide-3-Kinase (PI3K) Pathway and SSR Asthma
Increased PI3K-p110α levels can cause decline in the RA-inducible gene-I, interferons, and inflammatory cytokine responses subsequently invoke pathophysiological exacerbation in airway inflammation and enhance the susceptibility to viral infection. PI3K axis can be a therapeutic target in steroid resistant asthma due to its substantial role in modulating the levels of inflammatory cytokines in the asthma patients. 31 Several miRNAs have been implicated in the pathogenesis of asthma. 33,34 For instance, the miR-21 is known to be important in allergic airways disease (AAD) pathogenesis. The miR-21-deficient (miR-21−/−) mice with AAD are associated with decline in the eosinophilic inflammation and IL-4 levels, and elevated IFN-γ responses. 33,35 Biological network-based transcriptome analysis of OVA (ovalbumin)-challenged miR-21−/− mice determined that dysregulation of IL-12/IFN-γ plays a significant role in the observed phenotype and miR-21 considered as a key regulator of IFN-γ signalling and T-cell polarization. Thus, the loss of miR-21 augments T-helper cell type 1 (Th1)-related delayed hypersensitivity. 36 Interestingly, miR-21 can induce downregulation of PTEN expression, an endogenous suppressor of PI3K. 37 A study by Kwak et al 37 demonstrated that the mice with ovalbumin (OVA)-induced AAD mitigated PTEN levels across bronchiolar epithelial layer; the adenovirus-mediated overexpression of PTEN in AAD resulted in the increased IL-4 and IL-5 levels in the airways and reduced airway hyper-responsiveness (AHR). Furthermore, intratracheal administration of pharmacological pan-PI3K inhibitors could induce the impairment of bronchial inflammation and AHR in mice with AAD, which concluded the significant potential to implicate PI3K inhibitors (eg.wortmannin) to treat severe asthma. 38 Novel Treatment Strategies for mORC1-STAT3-FGFBP1, and SSR Asthma A recent study delineated the efficacy of poly-L-arginine in enhancing the asthma angiogenesis by modulating the mORC1-STAT3-FGFBP1 signaling in the airway epithelium but this pathway yet to be explored more during the SSR asthma in order to develop novel therapeutic targets to target this pathway. 39 Furthermore, the role of miR-21 has been observed to delineate pathogenesis of SSR asthma and previously deciphered its potential role to target Chlamydia, H. influenzae, influenza and Respiratory SyncystialVirus (RSV) infection-induced SSR asthma. 40 As per this study, miRNA-21 is an overexpressed gene in mouse models but the miR-21 expression in AAD is not reduced by steroid treatment. Additionally, the putative targets of miR-21 and PTEN expression are mitigated during upregulated expression of miR-21; these changes are associated with higher PI3K responses ( Figure 2). A significant association was observed between HDAC2 nuclear levels and the NR3C1 lung expression implicated in the SSR. Thus, a novel miR-21/PTEN/PI3K/HDAC2 signaling was described in the steroid resistant asthma. This was concluded by the administration of antagomiR-21, a miR-21 inhibitor, which impaired the lung miR-21 expression, and enhanced PTEN expression consequently mitigated PI3K activity, and enhanced HDAC2 levels. However, the antagomiR-21 can impair disease pathophysiology associated with severe SSR asthma.
This antagomiR-21 has not exhibited any effect on airway inflammation but retrieved the sensitivity to steroid treatment during severe steroid resistant allergic airway disease (SSRAAD). The treatment of pan-PI3K inhibitor LY294002 also impaired the SSRAAD features. Targeting miR-21 or PI3K could be considered as an effective way which can be implicated in the SSR asthma, eosinophilic asthma, and neutrophilic asthma or several other endotypes of SSR asthma. 40 Nanoformulations carrying these gene-based therapeutic miRNAs may effectively enhance the therapeutic window in the patients with SSR, which yet require substantial preclinical and clinical studies.
NLRP3 inflammasome formation significantly involved in the neutrophilic asthma; for instance, the higher NLRP3 and caspase-1 in airways enhanced IL-1β responses followed by the substantial rise in the Th17, and IL-17 generation implicated in AHR. [41][42][43][44][45][46] In addition, the NLRP3, caspase-1 and IL-1β responses could be extensively higher during the experimental models of SSR asthma induced through Chlamydia infection; 41 administration of NLRP3 inflammasome blocker, MCC950 could induce ameliorative effects in SSR asthma. So, the therapeutic molecules with nanoformulations which can target NLRP3 signaling might be a beneficial option to mitigate SSR asthma. Mepolizumab treatment can mitigate the requirement of oral steroids in severe eosinophilic asthma. 47,48 A specific link between innate type 2 inducers and TSLP (thymic stromal lymphopoietin), T-helper cells, with steroid resistance has also been reported. 49,50 In the following sections, we have vividly discussed the possible options of nanomedicine-based formulations, which could be implicated in the mitigation of pathophysiology of SSR.

Application of NDDS in Corticosteroid-Resistant Asthma
Novel Drug Delivery Systems NDDS are modern therapeutic options through different routes of administration for asthma treatment due to their salient features like target-specific drug action, prolonged release accompanied by specific targeted drug deposit, sustained release, biodegradability, decreased dosage frequency and lesser particle size; In addition, a higher surface area, enhanced solubility, stability, bioavailability making them a very good choice for the formulation scientists in formulating the drugs to treat heterogeneous diseases like asthma. NDDS includes liposomes, niosomes, nanoparticles, implants, solid lipid nanoparticles, polymeric micelles, dendrimers, and microparticles. Several nanomedicine based therapeutic formulations to mitigate the pathophysiology of SSR asthma or AAD were depicted in Figure 3. Application of NDDS to asthma is still in developmental stage, the operation of DDS in steroid resistant asthma is yet require substantial studies. The challenges in employing NDDS to asthma treatment and their implications in steroid resistance in asthma patients were described below.

Mucoadhesive Microparticles
The mucoadhesive polymer-based formulations are previously described for chronic obstructive pulmonary disease (COPD) but the efficacy of these formulations is yet to be explored against steroid resistant asthma as these mucoadhesive polymers possess a high affinity to mucosal surfaces. They possess amino groups in the chitosan, which can form electrostatic interactions with the amino groups of mucus's anionic groups; subsequently enhance the adhesiveness in order to release the drug moieties across the alveolar region during asthma conditions, which yet to be examined for the corticosteroid asthma. 51 Solid lipid microparticles (SLMs) mainly alginate and chitosan-based mucoadhesive SLMs can produce potential capability to form hydrogen bonding with mucin layers subsequently induce drug release. This strategy can be a remarkable strategy to treat asthma patients during corticosteroid therapy. 52 For instance, previous studies depicted the application of SLMs made of 3.5-4.0 μm induced the effective delivery of fluticasone across secondary bronchi for treating COPD. 52 Another study reported the delivery of budesonide mucoadhesive microparticles containing hyaluronic acid; these kinds of microparticles are in the range of 3.12-5.35 μm, and effectively inhalable range which can prolong T max and delay absorption, and prolong the budesonide retention. Furthermore, this phenomenon was also proven in inducing the higher bioavailability in an animal model because of hyaluronic acid's mucoadhesive ability. 53 However, these microparticles are very effective in delivering the antioxidant drug molecules through sustained release pattern, and the also enhancing the drug encapsulation efficiency, which could be an effective strategy to treat corticosteroid resistance in asthma patients.

Nanoparticles
In recent times, nanoparticles are employed to deliver drugs across the alveolar region of the lungs to mitigate the pathophysiology of several airway diseases. 54 For instance, the nanoparticles are mainly preferred for modulating the activity of endothelium cell adhesion receptors on endothelial lining of respiratory tract during asthma. In addition, the NADPH oxidase inhibitors, antioxidants such as SOD and CAT were formulated in the nanoparticles formulation for effective drug delivery across pulmonary airway in COPD or asthma. 55 Solid lipid nanoparticles (SLNs) are biocompatible and exhibit better stability when compared to liposomes. These are non-toxic when compared to polymeric nanoparticles, and production can be easily scaled up. By using meltemulsion method, Castellani et al formulated SLNs by melt emulsion technique with proanthocyanidins as a drug that reduced oxidative stress via lowering ROS generation. SLNs were nontoxic towards epithelial cells of respiratory tract. During in vitro studies, the uptake of SLNs with proanthocyanidins was better than those of drugs administered by conventional route of administration. 56 Carvalho et al formulated SLNs by fusion-emulsification technique with carvacrol as a drug that reduced the inhalational injury by decreasing malondialdehyde levels causing decline in the histopathological changes, which may be a potential implication in SSR asthma. SLNs typically exhibited polydispersed index of 0.126 ± 0.015 and average particle size of 78.72 ± 0.85 nm. 57 The limitations of SLNs could be uncertain drug release pattern and possibility of gelation (in case of polymorphism exhibited by solid lipids). 58,59 Hence, these patterns of SLNbased anti-asthmatic formulation can ameliorate the pathophysiology of SSR asthma when the therapeutic molecules combined even in multiple combinations.
Lipid-polymer hybrid nanoparticles (LPNs) possess similar features similar to that of polymeric nanoparticles and liposomes, in terms of stability aspects and biocompatibility. LPNs are composed of poly(lactic-co-glycolic acid) due to its substantial biodegradability; it can produce a suitable core to load several drugs including novel anti-asthma drugs. LPNs can effectively deliver drugs to cellular level . A study conducted by Thanki et al on H1299, lung carcinoma cell line with LPNs loaded with polylactic-co-glycolic acid, a biodegradable polymer and lipidoid showed gene silencing properties on the cell line. 60 LPNs were employed to deliver siRNA into the cell effectively as a part of therapy for COPD. 61 LPNs formulated with PLGA and an antioxidant Mn-porphyrin dimer (MnPD) were employed in treating COPD patients and showed higher HDAC2 levels inside the cell. 62 Lipidoid possesses the alkylated tetraamine backbone, many secondary and tertiary amines that makes easier interaction with anionic siRNA molecules. This kind of LPN-based drug formulation could be other alternate approaches to target SSR asthma. Simplification of preparation methods and effort to scale up LPNs production could be possible in the future perspective.
Theranostics, or the use of multifunctional nanomaterials that combine both therapeutic and imaging modalities, has brought a new age in current treatment techniques. 63 Silk fibroin nanoparticles can be prepared using a one-step desolvation process. To generate self-assembled CeNP-CD@SFSNPs nanocomposites, these anionic SFSNPs were combined with CeNPs and PEI-passivated carbon dots (CDs). The synthesized self-assembled CeNP-CD@SNPs-based nanocomposite could effectively minimize the oxidative stress in allergic asthma conditions when formulated with sulfarophane, which can lower ROS levels. 64 Such multifunctional nanocomposites could be great choices for delivering medications to the patients to prevent oxidative stress while also beneficial to mitigate disease pathophysiology including SSR asthma.
Nanotechnology adds a new dimension to customized medication delivery, with several advantages in COPD. However, nanomaterials for therapeutic delivery must be investigated for possible health risks, particularly as distinct NPs are reported to induce toxicity in proportion to their nanometer size, spawning a new area called nanotoxicology. 65 Through direct and indirect biological interactions, NPs also contribute to oxidative stress. The interaction of https://doi.org/10.2147/IJN.S364693

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International Journal of Nanomedicine 2022:17 nanoparticles with interior cellular components can cause oxidation, which worsens the severity of oxidative stress. NPs may also interact with cells indirectly, regulating ROS generation and modulate cellular phagocytic activity and oxidative burst. The oxidative stress generated by silica (SiO 2 ) nanoparticles was studied by Liu et al. The fluorescent probe DCFH-DA was utilized to measure the fluorescence intensity and detect ROS. Remarkably, the fluorescence in cells exposed to silica NPs was 1.7 times greater than in cells exposed to micro-sized SiO 2 particles. The study found that cells exposed to silica NPs suffered significantly higher oxidative damage than A549 cells exposed to micronized silica. 66 Because silica NPs are smaller and have a greater surface area, they can interact with cellular or subcellular structures more efficiently. However, there is a high amount of evidence accumulated pertinent to the toxicity, which suggests that NPs can cause oxidative stress. When creating nanoparticles for the treatment of oxidative stress-related asthma, or SSR asthma, it is crucial to ascertain NPs-induced toxicity and oxidative stress.
Formulation innovations pertinent to NPs offer a powerful methodology for drug conveyance in asthma conditions. Nonetheless, a few issues still need to be settled before its utilization in a clinical setting. Until this point in time, no clinical investigations utilizing NPs in the treatment of oxidative stress have been enrolled in the 'clinical trials.gov' information database. NPs cannot be straightforwardly utilized for the inhalation since they are not in the ideal size range for inward breath (optimal middle mass streamlined measurement (MMAD) for the statement in the little aviation routes and alveoli of the lungs ought to be 1 to 5 µm). Moreover, NPs exhibit predominantly bigger surfaces, which may bring about an increment in their free energy and expand the association between particles. The substantial levels of association between nanoparticles can induce agglomeration of the therapeutic molecules, which is considered as one of the significant limitations in the implications of NPs in developing the anti-SSR formulations.
To resolve these issues, NPs could be formulated along with microparticles. The strong grid can forestall the connection between NPs, limit their versatility, and increment their drawn-out security. More significantly, it can further develop aerosolization properties for effective delivery of novel anti-SSR formulations.

Liposomes
Liposome-based formulations could also be effective therapeutic option in order to enhance the combinatorial drug release, bioavailability, biodegradability during COPD treatment. Hence, these formulations composed of lipid moieties which can have a very good compatibility across lung tissue and confer the effective intracellular delivery of drug molecules through fusion with plasma membrane lipids, receptor mediated endocytosis, and phagocytosis. [67][68][69] In addition, liposomes (Table 1) are also utilised to confer effective release of hydrophilic, hydrophobic, and amphiphilic antioxidants, and antioxidant enzymes to mitigate the oxidative stress-induced damage including asthma. 78 Yet, the efficacy of these kinds of formulations must be examined against SSR asthma.
For instance, the liposome-based formulations pertinent to 'antioxidant-containing liposomes' made of NAC, glutathione, tocopherol, SOD, CAT can be used as a therapeutic option for acute oxidant-related COPD. However, due to their unfavourable physicochemical properties, the efficacy of SOD and CAT is limited. Antioxidant efficiency of these enzymes is significantly higher by the liposome entrapment. 81 For example, the NAC loaded liposomes could induce a higher efficacy by mitigating the lung permeability index during acute (4-h) CEES induced injury; in addition, there was a significant reduction in the levels of pro-inflammatory mediators in bronchoalveolar lavage fluids in the lungs exposed to substantial levels of oxidants. 82 Curcumin-loaded liposomes combined with chitosan also synergistically exerted their efficacy against oxidant-induced lung damage. 83 Translating the liposome treatment into the clinical aspects has been facing a lot of challenges due to the limited delivery, relative fragility in disease treatment like COPD. Therefore, the synthesis of liposome formulations of the specific anti-asthmatics requires special attention to avoid the difficulties in drug delivery in SSR asthma. [84][85][86] Nanocomposite microparticles: SSR Asthma Nanocomposite microparticles (NCMPs) have been used in treating respiratory diseases including COPD in order to mitigate oxidative stress effectively. The NCMPs can be prepared by combining both nanoparticles and microparticles; they can undergo dissociation at physiological conditions into original nanoparticles and also maintain nanocarrier properties in order to deliver the drug moieties. 87,88 NCMPs combined with miR-146 formulated with PGA-co-PGL

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International Journal of Nanomedicine 2022:17 along with mannitol and leucine can enhance the therapeutic efficacy and bioactivity of miR-146a against COPD. 89 It is easier to maintain the structure of nanoparticles as NCMPs atomized suspension made using biodegradable polymers and could be an effective treatment for COPD. 89 Therefore, the extensive research studies requiring the formulation of the antioxidant molecules with a higher antioxidant capacity in the encapsuled NCMPs form can be considered as a very good therapeutic agent for SSR asthma to mitigate pathophysiology. Significantly higher FPF (51.33%) and MMAD of less than 5 µm of microparticles reported with the ability of NCMPs deposition across the lungs; but this kind of efficacy in drug delivery can be achieved by selecting suitable excipients, adjuvants, and drying parameters, and drug concentration. These strategies can enhance the longer tissue retention times, and sustained drug release, and substantial cellular update, which could be very effective NDDS to treat SSR asthma.
On the other hand, the drug-loaded nanoparticles embedded in the swellable microparticles can be another effective NDDS approach to enhance drug delivery across lung regions in COPD or SSR asthma conditions. For instance, the curcumin-loaded PLGA nanoparticles with pegylated chitosan can form hydrogel microspheres in the range of 3.1-3.9 nm, and 221-243 nm delivered the drug in a sustained manner with good biodegradation rate even upon substantial drug loading. These are easily respirable and exhibit low tendency to generate TNF-α and mitigated macrophage update. 90 Yet, the swellable microparticle delivery for lung diseases requires substantial research, mainly the formulated swellable microparticles with antioxidant therapeutic molecules.
Formulation of lipid-polymer hybrid nanoparticles (LPNs) can exhibit typically both nanoparticles and liposomes due to their physical stability, subsequently they can produce a good efficacy to foster in vivo cellular delivery. For instance, the lipidoid-modified LPNs ( Table 2) can effectively induce gene knocking effects in NSCLC cancer cells, H1229 and induce intracellular siRNA delivery in order to target gene expression related to COPD. 60 These lipidoid formulations contain secondary and tertiary amines for 61 the effective interaction with siRNA without changing their net charge of LPNs. Formulation of LPNs with PLGA core with antioxidant Mn-porphyrin dimers combined with cationic lipid (DOTAP) shell effectively binds with pHDAC2. This kind of formulation can easily mitigate oxidative stress due to the multi-antioxidative capacity of MnPD. 62 Therefore, the LPNs-based drug molecule formulation can mitigate the pathophysiology of SSR asthma comparatively with a higher rate of drug delivery than the formulations administered in the conventional dosage forms.
A tailored drug delivery can be attained by the formulations made of noble metals such as silver, gold, and inorganic elements such as carbon, silicon dioxide, and iron oxide through the formulation of nanoparticles (Table 2). These kinds of inorganic NPs can induce significantly higher biocompatibility through drug delivery across pulmonary regions for treating COPD. Cationic metallic NPs can be used for the delivery of genes as they can effectively bind to DNA/RNA as inorganic NPs are considered as the potential nanocarriers for treating COPD. 91 Gold NPs can deliver the drug formulations 92 across the endothelium as they can be easily formulated with antioxidant CAT, SOD; these inorganic NPs can protect drug formulations from proteolysis suggesting a significant therapeutic approach to treat SSR asthma due to their efficacy in inducing anti-oxidant and anti-inflammatory effects in animal models of acute inflammation or oxidative stress. 86 The findings revealed that SOD/CAT and the nanocarriers work together to give a synergetic antioxidant effect. Nonetheless, in vivo research is needed to further investigate this strategy. 93 Activity of endothelial cells can be modulated using antioxidant enzyme nanocarrier formulation to induce anti-inflammatory effects.
Inorganic nanoparticles exhibit inherent oxidant-producing capabilities. However, these limitations can constrain their usage but the formulation of antioxidant inorganic NPs could prevent NPs induced oxidative damage. Another significant strategy is the dendrimers-type of NPs which can easily release drug moieties across the lungs and the dendrimers can be made of the polymers such as "poly(amidoamine) (PAMAM), ploy(L -lysine) (PLL), polyamides, polyesters (PGLSA-OH), polypropylenimine (PPI), ploy (2,2-bis(hydroxyl methyl) propionic acid), and polyethers". 106 These formulations can mitigate toxicity, and increase pharmacokinetic profiles as well as the aqueous solubility when combined with PEGylation. For instance, the PEGylatedpoly(lysine) dendrimers could be referred to as the effective pulmonary delivery agents due to their ability to induce longer drug retention across the lungs; futher, they can enable effective biodistribution for regulated drug delivery in passive circulation. 91,107 PAMAM dendrimers which have been shown to deliver

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International Journal of Nanomedicine 2022:17 biomacromolecules resembling siRNA. 108,109 This kind of formulation strategies also can enhance the longer drug retention during the treatment of COPD or SSR asthma.
Another formulation strategy such as microparticulate powders designed in dimethyl fumarate, an Nrf-2 activator was formulated to treat pneumonitis. These are spray dried particles and utilize the D-mannitol as a spray execution enhancer due to MMAD and a thin molecular portion of 49%. This was proven effective in inducing ameliorative effects by treating COPD, and these forumation strategies yet to be examined against asthma. 110 A comparative efficacy of co-spray dried powder was described by Trotta et al. In their review, inhalable microparticles containing budesonide, and resveratrol were described to create a multi drug inhalable plan for the treatment of COPD. 111 This kind of formulation strategy against SSR asthma also can mitigate the underlying pathophysiology. The planning of microscale powder is basic and simple to increase in this formulation but drug stacking and brief term of activity are normally experienced difficulties. 112

Translation of the NDDS from Bench Side to Bedside in SSR Asthma Patients
The lungs can act as a filtration unit removing all the pollutants and also harmful microbes thus protecting the respiratory system and also have a very composite structure. The lungs play a crucial role in the normal functioning of the respiratory system thus sometimes deposition of NPs is a problem for several functions like air humidification, temperature control across the thoracic and tracheobronchial regions, and gas exchange in the alveolar-interstitial region. Thus, the deposition of the NPs must cross the several barriers across lungs and also the physiology of lungs with high humidity (around 90%) during the phase of respiration may have interference with deposition and particle size. Initially, NCMPs need to attain the bloodstreams by moving across the lung obstruction; NCMPs tend to get retained by the lungs for longer duration which are associated with lining fluid or cells; and they are engulfed by macrophages in the phagocytosis process. Thus, the distribution of NPs must overcome several obstructions like epithelial tight junctions, immunological cells, and lung lining fluids must reach in order to induce sustained drug release.
Oxidative stress in COPD or SSR asthma can be treated with the help of inhalable microparticles. Several clinical studies have been conducted recently to prove the effectiveness of the inhalable microparticles. Particle replication process has been used in non-wetting Templates (PRINT) by Dumont et al to create uniform size and shaped dry powder microparticles which are undergoing Phase I clinical trial study. Ribavirin can be delivered effectively to the lung by two new inhalation formulations (Ribavirin-PRIN-CFI and Ribavirin-PRINT-IP) which can also minimize the bystander exposure. These can be examined against SSR asthma in order to mitigate the pathophysiology.
The main treatments of SSR asthma are the therapies to reduce the oxidative stress and drugs against inflammation. But frequent usage of the steroidal anti-asthmatic drugs could result in harmful side effects due to the development of steroid resistance. To minimize the associated side effects, safe and effective sustained release drugs should be used so that the drug administration could be minimized. In order to achieve the sustained release of drugs, the preparation of these drug molecules should be made in the form of biodegradable microparticles or NPs or other liposome-based nanoformulations which are required for the delivery to the pulmonary region.

Limitations
Normal surfactant-based drug delivery systems exhibit significant disadvantages of attaining premature drug releases due to the formation of micelle disruption if the micelle concentration declined below the critical micellar concentration. 113 In case of spongosomes, and cubosomes, there are significant challenges observed in order to improve the loading capacities for enhancing the therapeutic window. 113 Defects in the overall drug penetration are one of the prominent limitations when using nanoparticles in treating several diseases including cancers; this is due the perivascular accumulation and slow release, which consequently confer to the hindrance for effective drug delivery.

Conclusion
SSR asthma is a significant clinical problem and it should be addressed with the aid of more effective and competent therapies in those patients who are not responsive to the mainstay corticosteroid therapies. SSR asthma is also linked to the bacterial, viral respiratory infection, and the high-fat diet/obesity. Therefore, the strategies to target the signaling pathways such as mORC1-STAT3-FGFBP1, NLRP3 inflammasomes, miR-21/PI3K/HDAC2 axis, PI3K pathways with the aid of novel nanomedicine-based formulations may mitigate pathophysiology of SSR asthma and enhance the clinical outcomes.Several nanomedicine based formulations yet to be examined in the future studies against SSR asthma in order to identify and characterize their roles through therapeutic targeting.

Summary
• Immune signaling heterogeneity pertinent to the pathophysiology of SSR asthma is a predominant obstacle to choose efficient therapeutic modalities to overcome steroid resistance. • The mORC1-STAT3-FGFBP1, NLRP3 inflammasomes, miR-21/PI3K/HDAC2 axis, PI3K pathways could contribute to the alterations in the immune heterogeneity during SSR asthma. • Novel nanomedicine-based formulations may mitigate pathophysiology of SSR asthma by modulating immune heterogeneity and enhance the clinical outcomes.

Future Directions
As we discussed the immune repertoire of SSR, the exacerbation of SSR is exemplified by the presence of several specific cytokines such as IL-17, and IL-33 or immune effector elements, which could be used as specific molecular markers or therapeutic targets to treat SSR. A detailed investigation yet considered as unmet need in the clinical sector to prefer a personalized therapy for treating SSR. Albeit the respiratory system is highly accessible to several therapies to treat respiratory diseases, the gene therapy can satisfy the colloidal stability across the physiological fluids but may not overcome nucleases-mediated degradation. Therefore, nanomedicine-based delivery vectors may confer protection against degradation of these therapeutics when treating chronic respiratory diseases. In this scenario, several nanomedicine-based formulations yet to be examined in the future studies against SSR asthma in order to identify and characterize their roles through therapeutic targeting against Th2 transcription factors, and cytokines. Recently stem cell-based exosomes in the nanotherapeutic formulation have been explored for treating autoimmune diseases. 114 For instance, the proteomic characterization is required to explore the pharmacological mechanisms and efficacy of these molecules against SSR.