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Chemoresistance is one of the leading causes of therapeutic failure in gastric cancer (GC) treatment. Recent studies have shown lncRNAs play pivotal roles in regulating GC chemoresistance. Nanocarriers delivery of small interfering RNAs (siRNAs) to silence cancer‐related genes has become a novel approach to cancer treatment research. However, finding target genes and developing nanosystems capable of selectively delivering siRNAs for disease treatment remains a challenge. In this study, a novel lncRNA TMEM44‐AS1 that is related to 5‐FU resistance is identified. TMEM44‐AS1 has the ability to bind to and sponge miR‐2355‐5p, resulting in the upregulated PPP1R13L expression and P53 pathway inhibition. Next, a new nanocarrier called chitosan‐gelatin‐EGCG (CGE) is developed, which has a higher gene silencing efficiency than lipo2000, to aid in the delivery of a si‐TMEM44‐AS1 can efficiently silence TMEM44‐AS1 expression to synergistically reverse 5‐FU resistance in GC, leading to a markedly enhanced 5‐FU therapeutic effect in a xenograft mouse model of GC. These findings indicate that TMEM44‐AS1 may estimate 5‐FU therapy outcome among GC cases, and that systemic si‐TMEM44‐AS1 delivery combined with 5‐FU therapy is significant in the treatment of patients with recurrent GC. [ABSTRACT FROM AUTHOR]