Biomimetic Epitope-Imprinted Nanogatekeepers on Mesoporous Silica for Tumor-Targeted Drug Delivery

Mesoporous silica nanoparticles (MSNs) are promising drug carriers for cancer therapy, yet their clinical utility is hampered by premature drug leakage and poor tumor specificity. To address these challenges, we developed a molecularly imprinted polymer (MIP)-gated nanoplatform (mMSN/DOX-MIP) using a CD73 epitope peptide (WELTILHTN) as a template. The ultrathin MIP shell (<1 nm), synthesized from <i>N</i>,<i>N</i>'-bis(acryloyl) cystamine and dimethylaminoethyl methacrylate, functions both as a biomimetic antibody for specific tumor targeting and as a stimuli-responsive gatekeeper. Under physiological conditions (pH 7.4), the MIP layer remains stable, restricting doxorubicin (DOX) leakage to <7% over 96 h. Conversely, in the tumor microenvironment (TME, 10 mM glutathione, pH 5.5), rapid degradation of the MIP shell triggers >90% DOX release within 48 h. <i>In vitro</i> studies demonstrate selective targeting of CD73-overexpressing 4T1 cells, with 4.5-fold higher cellular uptake compared to that of CD73-low TC-1 cells. <i>In vivo</i> evaluations in 4T1 tumor-bearing mice reveal prolonged circulation, enhanced tumor accumulation, and potent therapeutic efficacy, achieving 90% tumor growth inhibition with minimal systemic toxicity. The epitope imprinting further improves the tumor penetration and specificity. This work not only validates the dual functionality of MIP-gated MSNs in precise drug delivery but also highlights their translational potential for treating CD73-high malignancies by synergizing tumor-targeted recognition with TME-triggered release mechanisms.