Targeted inhibition of ITK activity with anti-CD3 antibody-modified calcium silicate nanoparticles loaded with novel 7H-Pyrrolo[2,3-d]pyrimidine derivatives for treating aplastic anemia.

Aplastic anemia (AA) is a debilitating disorder marked by bone marrow failure, frequently associated with dysregulated T cell activity. The present study explored the therapeutic potential of anti-CD3 antibody-modified calcium silicate nanoparticles loaded with novel   7H-pyrrolo[2,3-d]pyrimidine derivatives (antiCD3-pCaSiNP@NPDP) for AA treatment. Whole-transcriptome sequencing and bioinformatics analysis identified interleukin-2-inducible T-cell kinase (ITK) as a critical regulator of T cell function in AA. In vitro experiments demonstrated that ITK enhances T cell proliferation and promotes differentiation toward inflammatory subsets, thereby contributing to disease progression. The newly developed NPDP derivatives effectively inhibited ITK activity. Targeted delivery of NPDP via antiCD3-pCaSiNP nanoparticles selectively suppressed ITK expression in T cells, resulting in reduced inflammatory T cell proliferation and increased regulatory T cell populations. In an AA mouse model, administration of antiCD3-pCaSiNP@NPDP nanoparticles markedly improved hematopoietic recovery and immune balance. The findings indicate that nanoparticle-mediated ITK inhibition represents a promising therapeutic strategy for restoring immune and bone marrow function in AA.