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Mesoporous silica nanoparticles (MSNs) have emerged as promising drug carriers that can facilitate targeted anticancer drug delivery, but efficiency studies relying on active targeting mechanisms remain elusive. This study implements in vitro 3D cocultures, so‐called microtissues, to model a physiologically relevant tumor microenvironment (TME) to examine the impact of surface‐modified MSNs without targeting ligands on the internalization, cargo delivery, and cargo release in tumor cells and cancer‐associated fibroblasts. Among these, acetylated MSNs most effectively localized in tumor cells in a 3D setting containing collagen, while other MSNs did so to a lesser degree, most likely due to remaining trapped in the extracellular matrix of the TME. Confocal imaging of hydrophobic model drug‐loaded MSNs demonstrated effective cargo release predominantly in tumor cells, both in 2D and 3D cocultures. MSN‐mediated delivery of an anticancer drug in the microtissues exhibited a significant reduction in tumor organoid size and enhanced the tumor‐specific cytotoxic effects of a γ‐secretase inhibitor, compared to the highly hydrophobic drug in free form. This inherent targeting potential suggests reduced off‐target effects and increased drug efficacy, showcasing the promise of surface modification of MSNs as a means of direct cell‐specific targeting and delivery for precise and successful targeted drug delivery.

Abstract Multifunctional biomaterial inks are in high demand for adapting hydrogels in biomedical applications through three‐dimensional (3D) printing. Our previously developed xeno‐free system consisting of anionic cellulose nanofibers (T‐CNF) and methacrylated galactoglucomannan (GGMMA) as a photo(bio)polymer provides high‐performance ink fidelity in extrusion‐based 3D printing. The fusion between nanoparticles and this biomaterial‐ink system is a promising yet challenging avenue worth exploring, due to the colloidal stability of T‐CNF being sensitive to electrostatic interactions. Mesoporous silica nanoparticles (MSNs), with their robust ceramic matrix and fine‐tunable surface chemistries, are well‐established nanocarriers for different biologicals. Here, we fabricated MSNs with different surface modifications resulting in a net surface charge ranging from highly negative to highly positive to develop printable MSNs‐laden nanocomposite biomaterial inks. We utilized rheology as a comprehensive tool to address the matrix interactions with differently surface‐charged MSNs. Fluorescently labeled bovine serum albumin (FITC‐BSA) was used as a model protein for MSN loading, whereby negatively or neutral‐charged MSNs were found suitable to formulate FITC‐BSA‐loaded biomaterial inks of T‐CNF/GGMMA. Depending on the particles’ surface charge, FITC‐BSA showed different release profiles and preserved its stability after release. Lastly, the proof‐of‐concept to deliver large‐sized biological cargo with MSN‐laden nanocomposite biomaterial inks was established via the 3D printing technique.