Targeted Ganglion Delivery of CaV2.2-Mediated Peptide by DNA Nanoflowers for Relieving Myocardial Infarction and Neuropathic Pain

N-type calcium channel (CaV2.2) protein contributes to neuronal excitability and overactivation in sympathetic ganglion (SG) following myocardial infarction (MI), thereby easily triggering cardiac remodeling and ventricular arrhythmias (VAs). Despite much advances in the understanding of CaV2.2, a neuron-targeted modifying treatment is, yet, infrequently realized. Moreover, establishing a specific delivery strategy and stable probe architecture with an extensive molecular structure in pursuit of the complex CaV2.2 regulation still remains a challenge. Herein, we develop a smart DNA nanoflower (sDNF) composite by utilizing the customizable design and scalable production from a multifunctionality-encoded template that self-assembles into a biomimetic nanoarchitecture. The nanoarchitecture contains a neuron-targeting aptamer and a decorated CaV2.2 mediator peptide-DNA bioconjugate. The combined targeted delivery and the release of the CaV2.2 mediator peptide synergistically led to an ∼31% reduction of the peak calcium current in neuron cells. Moreover, sDNF alleviated MI-induced SG hyperactivity and improved in vivo outcomes, such as decreasing susceptibility to VAs and relieving neuropathic pain for 10 h. The infarct size treated with sDNF is reduced to approximately 11.1%. It is envisioned that the DNF-based nanostructure for cardiac remodeling suppression and VAs inhibition along with pain relief provides a potential approach for the clinical treatment of sympathetic-associated cardiovascular diseases.