Transmembrane DNA Nanochannel-Engineered Artificial Receptors for Navigating NK Cell Immunotherapy in Solid Tumors

Adoptive natural killer (NK) cell therapy for solid tumors faces critical challenges, including tumor antigen heterogeneity, impaired tumor infiltration, and suboptimal activation imposed by the immunosuppressive microenvironment. Here we developed an engineered nanoplatform featuring transmembrane DNA nanochannel-engineered artificial receptors (NCAR) to direct NK cells against solid tumors through two synergistic mechanisms: 1) Tumor Microenvironment (TME) Reprogramming: leveraging cholesterol-mediated insertion, NCAR incorporates into tumor membranes to disrupt phospholipid bilayers, inducing immunogenic cell death with the release of damage-associated molecular patterns (DAMPs; e.g., HMGB1, CRT), which remodels immunosuppression TME and recruits/activates NK cells. 2) Precision Targeting: NCAR forms programmable synthetic immune synapses with DNA nanoartificial ligands (NAL) engineered on NK cells via base-pairing. This antigen-independent assembly network establishes a universal membrane interface, enabling sustained tumor-targeted NK cell activation. The dual-component system enables sustained intratumoral accumulation of NK cells (>96 h), with a 15.1-fold increase in activated NKP46⁺GZB⁺ NK cells compared to controls. By bridging DNA nanotechnology with cell immunotherapy, our nanoplatform provides a universal strategy for navigating tumor-immune interactions, addressing key limitations of adoptive NK cell immunotherapy in solid tumors.