Helper T Cell (CD4⁺) Targeted Tacrolimus Delivery Mediates Precise Suppression of Allogeneic Humoral Immunity

Abstract

Antibody-mediated rejection (ABMR) is a major cause of dysfunction and loss of transplanted kidney. The current treatments for ABMR involve nonspecific inhibition and clearance of T/B cells or plasma cells. However, the prognosis of patients following current treatment is poor. T follicular helper cells (Tfh) play an important role in allograft-specific antibodies secreting plasma cell (PC) development. Tfh cells are therefore considered to be important therapeutic targets for the treatment of antibody hypersecretion disorders, such as transplant rejection and autoimmune diseases. Tacrolimus (Tac), the primary immunosuppressant, prevents rejection by reducing T cell activation. However, its administration should be closely monitored to avoid serious side effects. In this study, we investigated whether Tac delivery to helper T (CD4+) cells using functionalized mesoporous nanoparticles can block Tfh cell differentiation after alloantigen exposure. Results showed that Tac delivery ameliorated humoral rejection injury in rodent kidney graft by suppressing Tfh cell development, PC, and donor-specific antibody (DSA) generation without causing severe side effects compared with delivery through the drug administration pathway. This study provides a promising therapeutic strategy for preventing humoral rejection in solid organ transplantation. The specific and controllable drug delivery avoids multiple disorder risks and side effects observed in currently used clinical approaches.

Astaxanthin Activated the Nrf2/HO-1 Pathway to Enhance Autophagy and Inhibit Ferroptosis, Ameliorating Acetaminophen-Induced Liver Injury

“…At present, to overcome drug solubility obstacles and improve oral bioavailability, many drug delivery technologies have been developed. − Mesoporous silica nanoparticles (MSNs) are undoubtedly the best and most researched because of their excellent characteristics: ordered porous structure, large pore volume and surface area, tunable particle size, and good biocompatibility. , Over the past decade, MSN-based delivery systems for poorly soluble drugs, antitumor drugs, and therapeutic genes have made exciting progress. − Theoretically, the restriction of the cavity to water-insoluble drugs can reduce the crystallization of drugs, further reducing the lattice energy and thereby improving the dissolution and availability. , As a type of MSN, hollow mesoporous silica nanoparticles (HMSNs) have attracted attention in biomedical applications due to their large internal cavity and mesoporous shell. , The study found that HMSNs have a higher drug-loading capacity than the traditional MSN family, which reduces the potential accumulation of foreign bodies in the body. − For example, Gao et al found that modified PYR-HMS-HPC showed stronger functional activity against Magnaporthe oryzae than single pyraclostrobin formulations . Li et al and Lee et al used HMSNs as drug carriers for tumor multimodality imaging and therapy. , Several studies have evaluated the acute and subacute toxicity of low-dose and/or therapeutic doses of MSNs in tissues such as of the liver, spleen, kidney, heart, intestine, stomach, muscle, or lung, and no significant histological damage or pathological abnormalities were observed. − Recently, several studies reported that HMSNs mainly accumulated in the liver in vivo. , …”

Desialylated Platelet Clearance in the Liver is a Novel Mechanism of Systemic Immunosuppression

“…Conversely, increased dPLT hepatic targeting of detrimental antigens such as cancer aggregates or viral particles may protect them from immune targeting. Further studies are required to explore the full implications of this novel immunosuppressive pathway within different diseases [ 86 – 90 ].…”

Adaptive Design of Nanovesicles Overcoming Immunotherapeutic Limitations of Chemotherapeutic Drugs through Poliovirus Receptor Blockade

“…In recent years, nanomedicine, including cell membrane delivery systems, has become an important complement to disease treatment. − Cell membrane-derived nanodelivery systems, including extracellular vesicles, cellular membrane nanovesicles, and extracellular vesicles or cell membrane-coated nanoparticles have been successfully favored by several researchers. , The cell membrane-derived nanodelivery system is a phospholipid bilayer structure, mainly composed of lipids and proteins, which retain many cell-derived properties and important physiological functions. − Multiple types of cell membranes have been used to prepare nanodelivery systems for cancer treatment, which greatly promote the development of tumor treatment. − The NIH-3T3 cells are commonly employed as murine engineered cells because of their excellent biosafety profile and robust expression of exogenous genes.…”