CNC–PNIPAM Drug Delivery System Improves Endometrial Receptivity via Natural Killer Cell Immune Tolerance in Endometriosis

Endometriosis (EM) results in pelvic adhesions and chronic inflammation, which significantly reduce embryo implantation and the clinical pregnancy rates of in vitro fertilization (IVF), affecting 190 million women worldwide. Traditional hormonal and surgical treatments alter ovarian and endometrial function, thereby hindering IVF. An urgent need exists for a localized treatment strategy that does not interfere with IVF procedures, aiming to enhance endometrial receptivity. To address this, we developed an innovative localized drug delivery system that simultaneously targets immune dysregulation and enhances endometrial function. This study reports a dual‐drug delivery system based on poly(N‐isopropylacrylamide) (PNIPAM) combined with nanocrystalline cellulose (CNC) for the local release of levonorgestrel (LNG) and botropase (BTP) to reprogram uterine natural killer cells and treat EM, overcoming previous drawbacks. The experimental results confirm stable CNC and PNIPAM structures and controlled the release of the composite drug. At concentrations of 0.5 mg/L LNG and 100 mg/L BTP, the release system achieved the highest CD16 – /CD16 + ratio and the most pronounced upregulation of autophagy‐related molecules in uNK cells in our in vitro assays, indicating a shift in uNK cells toward an immune‐tolerant state. In a mouse model of EM, the CNC–PNIPAM drug delivery system significantly improve endometrial receptivity. The CNC–PNIPAM drug delivery system demonstrates the medical potential of the local release of composite drugs, offering a new immunomodulatory approach for the treatment of EM and broader medical applications.