Circularized Supramolecular Spherical Nucleic Acids Alleviates Liver Fibrosis through Blocking Upstream Activation and Reversing Activation State of Hepatic Stellate Cells

Inhibition of hepatic stellate cell (HSC) activation and reversal of its activation state represent two distinct yet complementary strategies in antifibrotic therapy. While synergy of those two strategies is anticipated to improve the therapeutic outcomes, synergism through nanomedicine remains elusive. Herein, we report a circular spherical nucleic acid (cSNA) with a supramolecular core comprising collagenase I and ML-290 and a surface attached with circular PDGF-BB aptamer instead of the stereotypical linear counterpart. Unlike conventional inert SNA, this cSNA core dissociates in response to elevated ROS levels in the fibrotic liver so that collagenase I is released to disrupt the collagen barrier to promote the penetration of ensuing nanoparticles. Of significant importance is that the PDGF-BB aptamer after circularization exhibits enhanced nuclease resistance and improved molecular recognition, thereby demonstrating superior capability in blocking HSC activation mediated by PDGF-BB/PDGFR-β signaling. Meanwhile, relaxin family peptide receptor 1 (RXFP1) agonist ML-290 initially transforms pro-fibrogenic macrophages into pro-resolution macrophages by activating RXFP1 signaling, facilitating the secretion of pro-resolution factors for the reversal of the activated state of HSCs. This work thus presents a proof-of-concept demonstration of a supramolecular SNA that undergoes structural and functional refinements, enabling concurrent upstream etiological blockade and downstream pathological restoration in liver fibrosis.