Lymph‐Node‐Targeted Drug Delivery for Effective Immunomodulation to Prolong the Long‐Term Survival After Heart Transplantation

Abstract

The chronic rejection responses and side effects of the systematic administration of immunosuppressants are the main obstacles to heart allograft and patient survival. The development of xenotransplantation also urgently requires more efficient immune regulation strategies. Herein, it is demonstrated that lymph‐node (LN)‐targeted drug delivery can realize LN‐specific immunomodulation with attenuated immune suppression on distant peripheral immune organs to effectively prolong long‐term survival after heart transplantation in a chronic murine heart transplantation model. A chemokine C‐C motif ligand 21 (CCL21) specific aptamer for LN targeting is decorated onto the surface of the hybrid nanoparticular delivery vector mainly composed of CaCO3/CaP/heparin. The targeting delivery system can dramatically enhance accumulation of the loaded immunosuppressant, fingolimod hydrochloride (FTY720), in draining lymph nodes (dLNs) for inducing powerful immune suppression. By promoting the generation of endogenous regulatory T cells (Tregs) and decreasing the proportion of effector T cells (Teffs) in dLNs after heart transplantation, the LN‐targeting strategy can effectively regulate local immune responses instead of systemic immunity, which reduces the incidence of long‐term complications. This study provides an efficient strategy to improve the survival rate after organ transplantation by precise and localized immunoregulation with minimized side effects of immunosuppression.

Mitochondrion-targeted carboxymethyl chitosan hybrid nanoparticles loaded with Coenzyme Q10 protect cardiac grafts against cold ischaemia‒reperfusion injury in heart transplantation

“…Among the many drug delivery systems, natural polymer/inorganic nanocomposites have become a research hotspot for drug delivery due to their simple preparation, controllable particle size, high biological safety, and various properties [ 35 ]. Hence, based on previous research in our laboratory [ 11 ], we proposed a novel mitochondrion-targeted nanocarrier for delivering CoQ10, which was synthesized by self-assembly in an aqueous medium using BCMC, carbonate ions, and phosphate ions as raw materials.…”

“…CoQ10@TNPs were successfully synthesized as we described earlier with slight modifications [ 11 ]. In brief, a mixture of 0.0106 g of Na 2 CO 3 and 0.0358 g of Na 2 HPO 4 ·12H 2 O was dissolved in 10 ml of ultrapure water.…”

Role of the Lymphatics in Cardiac Disease

“…Specifically, it is currently estimated that >50% of heart transplant patients will experience chronic cardiac allograft vasculopathy and nonspecific graft failure within 10 years following transplantation. 80,81 Vascular remodeling in allografts is known to result from immunologic rejection, which implicates the lymphatic system owing to its crucial role in the alloimmune response (immune response to nonself antigens). 82 During transplantation, donor lymphatic vessels are not anastomosed to that of the recipient.…”

“…87 Specific targeting of the lymph node, following long-term transplantation, using aptamer-coated nanoparticles has also been proposed resulting in increased survival and decreased immune cell infiltration, fibrotic response, and luminal narrowing. 81 Furthermore, this strategy primarily impacted local immune responses, as opposed to the systemic immune system, with specific lymph node immune environment alteration, thus reducing long-term global complications of treatment, which are common with immunosuppression. 81 Further research into more specific and effective immune regulation strategies remains necessary.…”

“…81 Furthermore, this strategy primarily impacted local immune responses, as opposed to the systemic immune system, with specific lymph node immune environment alteration, thus reducing long-term global complications of treatment, which are common with immunosuppression. 81 Further research into more specific and effective immune regulation strategies remains necessary. Taken together, promoting lymphangiogenesis could be beneficial to patients with HF to augment drainage and fluid homeostasis; however, the advent of new lymphatic vessels may be detrimental post-heart transplantation and interfering with lymphatic flow to the lymph nodes at time of transplant could improve graft survival.…”