Background: Achieving smart drug release and preventing premature leakage throughout the delivery journey are two crucial factors that are essential to take into account in the design of nanocarriers. Mesoporous silica nanoparticles (MSNs) can be modified with gatekeeper molecules to achieve controlled release behavior, making them highly promising nanocarriers for smart drug delivery purposes. Methods: Herein, we introduced a novel gatekeeper in the form of an inverted umbrella, consisting of a deferiprone (DFP)-copper complex, which was strategically immobilized on the surface of MSNs to facilitate smart and controlled release of doxorubicin (DOX) within tumor cells. Polyethylene glycol (PEG) polymer and aptamer were further added onto the surface of the nanocarrier to enhance its biocompatibility, and targeting capabilities. The physicochemical characteristics of the targeted nanoplatform, Apt-PEG-DOX@GNP, were investigated, and its anti-cancer effect was evaluated against C26 cells and CHO cells to assess its specificity. In order to evaluate the anti-tumor efficacy, possible side effects, and biodistribution of the prepared nanocarriers, the in vivo experiment was carried out on BALB/c mice bearing colorectal tumors. Results: The substantial surface area of MSNs, measuring 339 m2/g, facilitated effective encapsulation of DOX with a maximum loading 23 % ± 2.05. Preparation of Apt-PEG-DOX@GNP yielded uniform particles with an average diameter of 144.73 ± 11.29 nm. The Apt-PEG-DOX@GNP demonstrated iron-dependent release behaviors, wherein the cleavage of DFP−COOH-Cu(II) bonds decorating the silica nanoparticles occurred asynchronously, leading to the formation of new DFP− COOH-Fe(II) bonds for the subsequent release of DOX. The in vivo experiments revealed that the biocompatible nanocarriers displayed targeted toxicity towards C26 tumor bearing BALB/c mice, resulting in minimal side effects. Conclusion: Our prepared novel nanoplatforms showed promising potential for targeted treatment of colorectal cancer and precise control over the drug release.

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