*2.2. Synthesis of MSN-NH2in-Shout*

Two slightly different synthesis methods were used to prepare core-shell functionalized MSN containing 4.5% amino groups in the core and 2% thiol groups on the shell (MSN-NH2in-SHout).

Procedure A: Core-shell MSN particles were prepared by a co-condensation reaction according to our previous reports [17,43]. Early reports from our group showed that a consistent decrease in particle size can be obtained by decreasing the amount of TEA serving as organic base. This concept was applied for the synthesis of samples MSN160 nm, MSN130 nm and MSN100 nm [44]. A mixture of TEA (14 g, 93.8 mmol/10 g, 67 mmol/4 g, 26.8 mmol, respectively), tetraethylorthosilicate (TEOS, 1.74 mL, 7.84 mmol) and 3-aminopropyltriethoxysilane (APTES, 89 μL, 0.38 mmol) in a polypropylene reactor was heated in an oil bath at 90 ◦C for 20 min without stirring. A second solution was prepared consisting of water (2.41 mL, 1.21 mol), CTAC (2.71 mL, 1.83 mmol), TiPB (2.97 mL, 12 mmol) and ammonium fluoride (NH4F, 100 mg, 2.7 mmol) and was heated to 60 ◦C under stirring. The second solution was subsequently added to the first solution under strong stirring. The whole mixture was further stirred at room temperature for 20 min. After this time, four portions of TEOS (4 × 51 μL, 0.92 mmol) were added in three minute intervals and the solution was stirred for another 30 min. To prepare the shell layer, a premixed solution of TEOS (42 μL, 0.190 mmol) and mercaptopropyl triethoxysilane (MPTES) (42 μL, 0.22 mmol) was added to the whole mixture. The condensation reaction was allowed to continue over night at room temperature.

Procedure B: MSN80 nm and MSN60 nm were prepared using the tri-block copolymer F127 as a particle growth inhibitor/dispersant. The procedure is based on an adapted recipe reported in the literature [45]. First, a mixture of TEA (7 g, 46.8 mmol/4 g, 26.7 mmol, respectively), TiPB (1.5 mL, 6.2 mmol), F127 (100 mg, 8 μmol) TEOS (2 mL, 9 mmol), and APTES (89 μL, 0.38 mmol) was prepared in a polypropylene reactor and heated at 90 ◦C for 20 min. Separately, NH4F (100 mg, 2.7 mmol) and C18Br (0.35 g, 0.9 mmol) were dissolved in H2O. This solution was heated to 90 ◦C under static conditions for 30 min and was then added under strong stirring to the first solution at once. The combined solutions were further heated at 60 ◦C for 30 min. The ingredients for the shell layer, TEOS (42 μL, 0.190 mmol) and MPTES (42 μL, 0.22 mmol), were mixed, preheated to 60 ◦C and added to the reaction mixture. Heating at 60 ◦C was continued for 30 min, and then the reaction mixture was allowed to cool down to room temperature under stirring and was continuously stirred overnight.
