Engineering Stimuli‐Activatable Boolean Logic Prodrug Nanoparticles for Combination Cancer Immunotherapy

Abstract Prodrug nanoparticles that codeliver the immune modulators to the tumor site are highly recommendable for cancer immunotherapy yet remain challenging. However, effective stimuli‐responsive strategies that exploit the endogenous hallmarks of the tumor have paved the way for cancer immunotherapy. For the first time, the development of the Boolean logic prodrug nanoparticles (BLPNs) for tumor‐targeted codelivery of immune modulators (e.g., immune activator and immune inhibitor) and combination immunotherapy is reported herein. A library of stimuli‐activatable BLPNs is fabricated yielding YES/AND logic outputs by adjusting the input combinations, including extracellular matrix metalloproteins 2/9 (MMP‐2/9), intracellular acidity (pH = 5.0–6.0), and reduction (glutathione) in the tumor microenvironment. Tunable and selective control over BLPNs dissociation and prodrug activation is achieved by specifying the connectivity of orthogonal stimuli‐labile spacers while exploiting the endogenous signals at the tumor sites. The tumor‐specific distribution of the BLPNs and stimuli‐activation of the immune modulators for highly efficient cancer immunotherapy are further demonstrated. The results reported in this study may open a new avenue for tumor‐specific delivery of immune therapeutics and precise cancer immunotherapy.