CD47 peptide-albumin cloaked mesoporous silica nanoparticles for enhanced macrophage evasion and synergistic combination therapy

Upon introduction into the bloodstream, nanoparticles are rapidly enveloped by plasma proteins, forming a protein corona (PC) that typically accelerates their clearance via opsonization and macrophage uptake. However, specific proteins, such as albumin, exhibit dysopsonin properties, reducing sequestration and prolonging systemic circulation. In this study, we have developed a nanocarrier (DOX/Ce6@MSN-EMal-BSA/SP1) based on mesoporous silica nanoparticles (MSNs) coated with a light-responsive PC that prevents macrophage recognition and enables the controlled release of doxorubicin (DOX). The PC comprises bovine serum albumin (BSA) anchored to the MSN surface through a novel singlet oxygen-sensitive linker, with further functionalization using a CD47-mimetic peptide (SP1) to enhance immune evasion. BSA coating resulted in a 1.9-fold reduction in uptake by macrophage cultures compared to uncoated MSNs. Incorporation of SP1 further diminished macrophage internalization by 3.5-fold, as quantified by in vitro assays. Red light irradiation (660 nm) triggers cleavage of the singlet oxygen-sensitive linker, leading to PC shedding and subsequent DOX release. In vitro cytotoxicity evaluations against pancreatic cancer cell lines demonstrated potent efficacy: the nanocarrier exhibited an IC₅₀ of 0.99 μg mL⁻¹ against MIA PaCa-2 cells and 1.74 μg mL⁻¹ against PANC-1 cells. This high cytotoxicity is attributed to a synergistic effect (CI = 0.40 for MIA PaCa-2 and 0.17 for PANC-1) resulting from the photodynamic generation of singlet oxygen by chlorin e6 (Ce6) and the chemotherapeutic action of released DOX. These findings underscore the nanocarrier's potential for precision drug delivery in combination therapeutic modalities.