Biology subjects

Sankaran, K. R.

Publications and source records attributed to Sankaran, K. R..

4 recordsLinked to original sources

bioRxiv2026

A novel role for TRPV1 in macrophage giant cell formation

TRPV1 (transient receptor potential vanilloid 1) is a non-selective cation channel with high permeability to Ca2+ and is best known for its roles in sensory signaling. However, its function in immune cell biology, particularly in macrophage fusion, remains unknown. Cell fusion is a critical process in both physiological and pathological contexts, including development, tissue remodeling, and the foreign body response (FBR) to implanted biomaterials. During FBR, macrophages undergo fusion to form multinucleated foreign body giant cells (FBGCs), which contribute to implant degradation and fibrotic encapsulation. Here, we identify TRPV1 as a key regulator of macrophage multinucleation and FBGC formation. We demonstrate that TRPV1 is endogenously expressed in bone marrow-derived macrophages (BMDMs) and is upregulated in response to fusogenic cytokines and inflammatory stimuli. Functionally, TRPV1 promotes matrix stiffness-dependent macrophage adhesion and spreading, indicating a role in mechanosensitive signaling. We show that TRPV1 is required for efficient macrophage fusion under both cytokine-driven and matrix stiffness-mediated conditions. Mechanistically, TRPV1 links extracellular mechanical cues and cytokine signaling to cytoskeletal remodeling, facilitating the actin reorganization necessary for cell fusion. Importantly, TRPV1 deficiency does not alter TRPV4-mediated Ca2+ signaling, demonstrating that TRPV1 operates independently of TRPV4, a known mechanosensitive channel implicated in FBR and FBGC formation. Collectively, these findings suggest TRPV1 as a previously unrecognized mechanosensitive regulator of macrophage fusion and FBGC formation. This work provides new insight into the molecular mechanisms governing FBR and identifies TRPV1 as a potential therapeutic target for improving biomaterial biocompatibility and mitigating fibrosis.

cell biology↗

bioRxiv2026

A novel endosome-escaping, macrophage-targeted nanoparticle platform for miR-146a delivery with favorable in vivo biodistribution and biocompatibility

Advanced nanocarrier technologies have reshaped treatment paradigms for inflammatory and degenerative disorders by facilitating cell-specific delivery of bioactive molecules, including nucleic acids. Despite this progress, therapeutic application of microRNAs (miRs) has been hindered by rapid degradation, limited stability in circulation, and suboptimal cytosolic delivery within complex biological environments. In this study, we engineered and validated a macrophage-directed lipid nanoparticle (LNP) system designed to efficiently deliver the anti-inflammatory microRNA miR-146a (MacLNP-miR146a). Mannose-functionalized LNPs were generated through a scalable lipid injection formulation approach, producing highly uniform nanoparticles with strong physicochemical integrity across diverse pH conditions and in serum-rich environments. The optimized four-lipid composition supports efficient miR-146a encapsulation, promotes endosomal escape, and enhances intracellular trafficking, leading to effective cellular uptake and favorable tissue distribution in both in vitro and in vivo models. Notably, MacLNP-miR146a demonstrates strong biocompatibility in primary cell systems and animal studies. Together, these findings position MacLNP-miR146a as a robust and translational nanotherapeutic strategy for modulating macrophage-driven inflammation, including biomaterial-associated foreign body responses and related inflammatory pathologies.

bioengineering↗

bioRxiv2026

Endosome-escaping engineered LNP-miR146a with in vivo biodistribution to mitigate inflammation and foreign body giant cell formation

Nanomaterial-enabled delivery systems have transformed therapeutic strategies for treating inflammatory and degenerative diseases by enabling targeted delivery of small molecules and nucleic acids. However, the clinical translation of microRNA (miR) therapeutics remains limited by instability, enzymatic degradation, and inefficient intracellular delivery in biological environments. Here, we present the design and validation of a next-generation lipid nanoparticle (LNP) platform optimized for the stable and effective delivery of the anti-inflammatory microRNA miR-146a. This LNP system is produced using a scalable lipid injection-based formulation method and yields nanoparticles with uniform size distribution and exceptional physicochemical stability across a wide pH range (2.5-8) and in serum-containing conditions. The four-component lipid architecture enables high miR-146a loading efficiency, efficient endo/lysosomal escape, and robust cellular internalization, resulting in effective tissue uptake and biodistribution both in vitro and in vivo. Importantly, LNP-mediated delivery of miR-146a exhibits excellent biocompatibility and potent anti-inflammatory activity in primary cells and animal models. Collectively, these results suggest this LNP-miR146a platform as a stable, efficient, and translatable approach for modulating inflammation and addressing biomaterial-associated inflammatory responses.

bioengineering↗

bioRxiv2024

TRPV4-mediated Mechanotransduction Regulates the Differentiation of Valvular Interstitial Cells to Myofibroblasts: Implications for Aortic Stenosis

As aortic valve stenosis (AVS) progresses, the valve tissue also stiffens. This increase in tissue stiffness causes the valvular interstitial cells (VICs) to transform into myofibroblasts in response. VIC-to-myofibroblast differentiation is critically involved in the development of AVS. Herein, we investigated the role of mechanosensitive Ca2+-permeant transient receptor potential vanilloid 4 (Trpv4) channels in matrix stiffness- and transforming growth factor {beta}1 (TGF{beta}1)-induced VIC-myofibroblast activation. We confirmed Trpv4 functionality in primary mouse wild-type VICs compared to Trpv4 null VICs using live Ca2+ influx detection during application of its selective agonist and antagonist. Using physiologically relevant hydrogels of varying stiffness that respectively mimic healthy or diseased aortic valve tissue stiffness, we found that genetic ablation of Trpv4 blocked matrix stiffness- and TGF{beta}1-induced VIC-myofibroblast activation as determined by changes in morphology, alterations of expression of -smooth muscle actin, and modulations of F-actin generation. Our results showed that N-terminal residues 30-130 in Trpv4 were crucial for cellular force generation and VIC-myofibroblast activation, while deletion of residues 1-30 had no noticeable negative effect on these processes. Collectively, these data suggest a differential regulatory role for Trpv4 in stiffness/TGF{beta}1-induced VIC-myofibroblast activation. Our data further showed that Trpv4 regulates stiffness/TGF{beta}1-induced PI3K-AKT activity that is required for VIC-myofibroblast differentiation and cellular force generation, suggesting a mechanism by which Trpv4 activity regulates VIC-myofibroblast activation. Altogether, these data identify a novel role for Trpv4 mechanotransduction in regulating VIC-myofibroblast activation, implicating Trpv4 as a potential therapeutic target to slow and/or reverse AVS development.

cell biology↗