“Letter to the editor: nanomedicine delivery of anti-fibrotic sirnas in rare cardiac sarcoidosis: targeting granulomatous infiltrates”

Dear Editor,

Cardiac sarcoidosis (CS) is a serious inflammatory disease with a low incidence that is marked by granuloma infiltration in the myocardial tissue and results in fibrosis, arrhythmias, and heart failure. Although the immunosuppressive treatment advances have been made, the existing treatment methods are not specific and cannot prevent the progression of fibrosis, thus necessitating new ways of treatment. Nanomedicine with specific results such as targeted delivery of small interfering RNA (siRNA) to silence fibrotic gene expression is a prospective therapy to alleviate cardiac fibrosis in CS.

Recent transcriptomics studies have detected important fibrotic mediators like transforming growth factor-beta 1 (TGF beta 1) that is highly expressed in the granulomatous lesions in CS patients^[1,2]. Profiling of TGF B1 with siRNA is capable of inhibiting a profibrotic signaling cascade which can reverse reversing extra cellular matrix deposition and tissue stiffening. Kang et al. have shown that TGFb1 siRNA loaded into extracellular vesicles functionalized with fibroblast activation protein (FAP) aptamers can be selectively delivered to the injured cardiac tissues and induces cardiac repair in preclinical feats at a significant level^[2]. This localized treatment minimizes undesired effects and enhances delivery efficiency.

Another critical component of CS pathology is oxidative stress induced by Nox2-NADPH oxidase, which exacerbates inflammation and fibrosis. Somasuntharam et al used polyketal nanoparticles to transfect Nox2 siRNA, which worked well to restore the performance of the heart following myocardial infarction by alleviating oxidative stress^[3]. Anti-TGF1 therapy combined with the use of leveraged nanocarriers selective to granulomatous infiltrates in CS would synergize and reduce oxidative damage and fibrogenesis.

The wasting nanoplatforms like genetically programmed biomimetic ATP-detecting nanozymes are further improved to make therapeutic processes more precise, dynamically adjusting the fibrotic microenvironment. Li et al demonstrated that responsive nanozyme activation in pathological tissues was successfully reversed to restore cardiac fibrosis, which showed that a combination approach with siRNA delivery systems could be used in CS^[4].

Preclinical cardiac sarcoidosis modeling is problematic. Recently, Ruhparwar and Kellenbach have created a reproducible mouse model of CS with carbon nanotubes to cause granulomatous inflammation that was similar to human pathology^[5]. These models are essential in the study of the effectiveness and safety of nanomedicine-based siRNA therapies before they are translated to the clinical.

Conclusively, it is highly promising when nanomedicine delivers anti-fibrotic siRNAs that attack granulomatous inflammation in sarcoidosis of the heart. It is possible that using specific siRNA of TGFbc1 and oxidative mediators, unique nanocarriers, and disease models will help us to overcome the existing therapeutic constraints and enhance patient outcomes. More studies that combine these developments are justified to convert nanotherapeutics into a clinical therapy that will cure this rare but life-endangering disease. Our work is in line with the TITAN Guidelines on the need for transparency in AI use in healthcare^[6].

Ethical approval

Ethical approval was not applicable.

Source of funding

None.

Author contributions

All the authors meet the ICMJE authorship criteria and have made significant and equal contributions to this manuscript. All authors approved the final version and agree to be accountable for all aspects of the work, ensuring the accuracy and integrity of the data and interpretation.

Guarantor

All authors have read and approved the final version of the manuscript. They took complete responsibility for the data’s integrity and the data analysis’s accuracy.

Conflicts of interest disclosure

The authors declare no conflict of interest.

Data availability statement

Data sharing does not apply to this article as no datasets were generated during the current study; all data were sourced from published literature.

Transparency statement

The authors affirm that this manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted, and that any discrepancies from the study as planned (and if relevant, registered) have been explained.

Declaration of whether any AI was used in the research and manuscript development

None.