*2.2. Chemical Synthesis of Tyrosine-Modified PPI*

For the tyrosine-modification of the PPI G4 dendrimer, Boc (*tert*-butyloxycarbonyl) protected tyrosine (0.282 g, 1.0 mmol) was dissolved in 3 mL dry DMSO in a glass vial and PyBOP (0.616 g, 1.18 mmol) was slowly added and stirred for 15 min. In a separate glass vial, the PPI G4 dendrimer (0.1 g, 0.9 mmol in primary amines) was dissolved in dry DMSO and DIPEA (200 μL, 0.151 mol) was added. Next, the pre-activated tyrosine mixture was slowly added to the PPI solution and stirred for 48 h at room temperature. Thereafter, DMSO and other low molecular weight impurities were removed by dialysis (MWCO 1 kDa) against methanol for 6 h. The methanol was removed *in vacuo* and the modified dendrimer was dissolved in 5 mL TFA and left stirring overnight to remove the Boc group. Excess TFA was then removed by co-evaporation with methanol. Finally, the crude polymer was dissolved in 0.1 M HCl and excessively purified by dialysis against 0.05 M HCl for 24 h, then against water for 48 h with intermediate water exchange. Lyophilization yielded the tyrosine-modified PPI as white/yellowish fluffy powder. The degree of substitution was confirmed by 1H-NMR (Avance III, 400 MHz, Bruker BioSpin, Rheinstetten, Germany) and calculated as described in [35], indicating an almost complete tyrosine functionalization of the outer primary amines. 1H-NMR (400 MHz, D2O) δ 1.47–2.17 (m, PPI, 4.023 H), 2.45–3.37 (m, PPI +CH2 tyrosine, 9.38 H), 3.93 (m, CH tyrosine, 1 H), 6.86–6.88 (d, HAr tyrosine, 2H), 7.11–7.13 (d, HAr tyrosine, 2H).

The tyrosine-modified 5 kDa and 10 kDa branched PEIs (P5Y, P10Y) and linear PEIs (LP5Y, LP10Y) were prepared as described previously according to similar protocols [50,54].
