In this research, we developed an endosomal pH‐responsive NP system that targets the unique microenvironment of the tumor to systematically deliver SERPINB3 siRNA to HNSCC tumors in vivo and found that SERPINB3 silencing effectively restored sensitivity to cisplatin in patient‐derived xenografts (PDXs) from HPV‐negative HNSCC patients (Scheme 1). The gene discussed is SERPINB3; the disease is head and neck squamous cell carcinoma.