*3.1. Particle Synthesis*

We synthesized a series of core-shell MSNs with uniform size, ranging from 60 to 160 nm via a delayed co-condensation method [17]. The core of all MSNs was functionalized with 4.5 mol% APTES (with respect to total silica) carrying amino groups in order to create a positively charged inner void volume capable of encapsulating the negatively charged RNA by electrostatic interaction. The outer surface was functionalized with 2 mol% mercaptopropyl triethoxysilane (MPTES) carrying a thiol functionalization to act as regiospecific linker for external binding of polymer and targeting ligand.

Two slightly di fferent approaches were used to modulate the particle size of MSNs and to prepare a series of MSNs with uniform sizes over a range from 60 to 160 nm. Larger particles with average particle sizes of 160, 130 and 100 nm (MSN160 nm, MSN130 nm and MSN100 nm) were synthesized based on our previous reports using a decreasing amount of the base triethanolamine (TEA) in order to reduce the particle size (experimental details are described in the Materials and Methods section) [43,44,46]. Briefly, to prepare the core of our core-shell particles, a preheated solution containing cetyltrimethylammonium chloride (CTAC) as template and triisopropylbenzene (TiPB) as pore-expanding agen<sup>t</sup> was mixed with a preheated solution containing TEA, tetraethoxysilane (TEOS) and APTES at an elevated temperature for 20 min. This was then followed by addition of the ingredients for the surface layer containing TEOS and MPTES. To prepare smaller particles with average particle sizes of 80 and 60 nm (MSN80 nm and MSN60 nm), we applied a slightly di fferent procedure, additionally using F127 as growth inhibitor/pore expanding agen<sup>t</sup> according to published reports [45]. The particle size and core-shell structure were then established as above, again by changing the molar ratio of TEOS:TEA. Hereby, a preheated solution of octadecyltrimethylammonium bromide (C18Br) as template was mixed with a second preheated solution of TiPB, F127, TEA, TEOS and APTES, and stirred at 60 ◦C for 30 min. Afterwards, premixed TEOS and MPTES were added to form the negatively charged shell layer.
