AbstractIn the context of cancer therapy, a recently identified therapeutic target is represented by the essential subtype of RNA transcripts ‐ the long noncoding RNAs (lncRNA). While this is the case, it is especially difficult to successfully regulate the expression of this subtype in vivo, particularly due to the protection granted by the nuclear envelope of nuclear lncRNAs. This study documents the development of a nucleus‐specific RNA interference (RNAi) nanoparticle (NP) platform for the targeted regulation of the nuclear lncRNA function, in order to effectuate successful cancer therapy. An NTPA (nucleus‐targeting peptide amphiphile) and an endosomal pH‐responsive polymer make up the novel RNAi nanoplatform in development, which is capable of complexing siRNA. The nanoplatform is capable of accumulating greatly in the tumor tissues and being internalized by tumor cells, following intravenous administration. The exposed complexes of the NTPA/siRNA may conveniently escape from the endosome with the pH‐triggered NP disassociation, following which it can target the nucleus by specifically interacting with the importin α/β heterodimer. In orthotopic and subcutaneous xenograft tumor models, this would result in a notable suppression of the expression of nuclear lncNEAT2 as well as greatly impede the growth of tumors in liver cancer.