Lock‐and‐Shield Strategy Enables Stable and Stimuli‐Responsive Tumor‐Targeted Gene Delivery

Abstract A major challenge to effective cancer gene therapy is the absence of delivery systems that both protect nucleic acids in circulation and release them efficiently inside tumor cells. Nucleic acids are rapidly degraded by nucleases, cleared from the blood, and poorly internalized due to size and charge. Existing vectors address parts of this problem but remain limited by cytotoxicity, instability, or inadequate tumor selectivity. Here, a lock‐and‐shield strategy integrating a hyaluronic acid Nanogel with a hybrid membrane shell (Nanogel@hMVs) is reported. The Nanogel “lock” physically entraps nucleic acids with high efficiency (81.6%–89.2%) and incorporates dual pH/redox‐responsive linkers for controlled release under tumor‐associated conditions. The membrane “shield”, derived from tumor cell membranes and fusogenic lipids, reinforces systemic stability, preserves homotypic recognition, and mediates fusion‐driven cytosolic entry, ensuring tumor‐selective and efficient intracellular delivery. Nanogel@hMVs remain stable for 30 days, promote efficient uptake with minimal lysosomal sequestration, and silence Survivin. Across DNAzyme, siRNA, and ASO, they consistently produce potent gene silencing and in vitro antitumor activity. In vivo systemic administration yields preferential tumor accumulation, marked tumor inhibition, and prolonged survival without detectable toxicity. Collectively, Nanogel@hMVs establish a robust, safe, and adaptable lock‐and‐shield platform for systemic nucleic acid delivery in cancer therapy.