Proposed mechanisms of the reduced activation of G3139 in RIT-INPs. The recognition of G3139 by TLR9 mainly in late endosomes activates NF-κB pathway due to the CpG motifs in the G3139 sequence, thereby up-regulating its downstream target antiapoptotic proteins and inducing cytokine release. We present a new strategy of using INPs to control endosomal compartmentalization of ONs using the preserved signaling from antibodies on INPs. The early endosomal retention of liposomal nanoparticles and the cross-linking effect of rituximab lead to the reduced activation of G3139 in RIT-INPs, thus enhancing their gene-silencing effects in leukemic cells in vitro and in vivo.