SUPPLEMENTARY INFORMATION. For

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1 Eletroni Supplementry Mteril (ESI) for Journl of Mterils Chemistry B. This journl is The Royl Soiety of Chemistry 217 SUPPLEMETARY IFRMATI For Phyoynin-bsed nnorrier s new nnopltform for effiient overoming of ner drug resistne Results A B 8 Intensity (perent) μm 1 1 Size (d. nm) C Totl ounts 1 FA-PCP@DX 8 6 FA-PCPs 4 2 PCPs Zet potentil (mv) D Size (d. nm) Time (d) Figure S1. (A) TEM imge of PCPs. (B) Size distribution of PCPs. (C) Zet potentil of PCPs, FA-PCPs nd FA-PCP@DX. (D) Size vrition of PCPs in queous solution monitored for 35 dys. Vlues expressed were mens ± SD of 3 independent experiments.

2 H 2 H H H H H H 2 H H H H 4 H 3C H CH 3 CH 3 (A) (B) mau 3 t=11.9 min mau 3 t=13. min (min) (min) (C) (D) [2M+H] [2M] [M+EDC+H 4] [M+H] + [M-C 5H 7 4+H 4] [M] Figure S2. HPLC spetr of ompound (A) FA nd (B) FA-EDC. The ESI-MS spetr of ompound (C) FA nd (D) FA-EDC. A B FA-PCP@DX PCPs FA-PCPs FA DX Wvenumber (m -1 ) Wvenumber (m -1 ) Figure S3. (A) FT-IR spetr of PCPs, FA-PCPs nd FA-PCP@DX. (B) FT- IR spetr of FA nd DX.

3 A 1 μm B Intensity (perent) Size (d. nm) Figure S4. (A) TEM imge of FA-PCP@DX. (B) Size distribution of FA- PCP@DX. 3 DX FA-PCP@DX IC 5 (μm) 2 1 Figure S5. The ytotoxiities of FA-PCP@DX or DX towrds RHepG2, RMCF-7, Hel, MCF-7, HepG2, A375, HUVEC nd L2 ells for 36 h. Vlues expressed were mens ± SD of 3 independent experiments.

4 A Fluoresene intensity B Uptke effiy (%) 8 4 h 8 h FA (mg/ml) FA (mg/ml) FA-PCP@DX (5μM) * C 15 Vibility (%) 1 5 b FA FA-PCP@DX (1 μm) Figure S6. (A) The fluoresene intensity of FA-PCP@DX in RHepG2 ells fter bloked with exess mount of FA. The ells pretreted with different onentrtions of FA for 1 h were subjeted to 5 μm FA-PCP@DX tretment for 3 h. The fluoresene of FA-PCP@DX in the ells ws determined with the exittion nd emission wvelength t 485 nm nd 59 nm respetively. (B) The uptke effiieny of FA-PCP@DX in RHepG2 fter treted with exess FA.25 mg/ml. 5 μμ FA- PCP@DX ws initilly fed to the RHepG2 ells. At the time point of 4 h nd 8 h, the uptke effiieny of FA-PCP@DX ws mesured. * indited the sttistil differene of uptke effiy in the time point of 4 h nd 8 h t P <.5 level. (C) The ytotoxiity of FA-PCP@DX in RHepG2 ells fter treted with exess FA (.25 mg/ml). The ell vibility ws mesured fter 24 h of FA-PCP@DX tretment. Different letters represented signifintly different mens in three or more groups (P <.5, Tukey s test, one-wy AVA). Vlues expressed were mens ± SD of 3 independent experiments.

5 Perentge (%) b Figure S7. Intrellulr uptke of FA-PCP@DX in RHepG2 ells with the pretretment of different endoytosis inhibitors. Different letters represented signifintly different mens in three or more groups (P <.5, Tukey s test, one-wy AVA). Vlues expressed were mens ± SD of 3 independent experiments.

6 A Vibility (%) Vibility (%) DG FA-PCP@DX C b b B Vibility (%) 1 5 Dynsore FA-PCP@DX D Vibility (%) 1 5 b b ysttin FA-PCP@DX Surose FA-PCP@DX Figure S8. The pretretment of 3 /DG, dynsore, nysttin nd surose deresed the ytotoxiity of FA-PCP@DX (1 μm) in RHepG2 ells t 24 h of tretment. Vlues expressed were mens ± SD of 3 independent experiments. Different letters represented signifintly different mens in three or more groups (P <.5, Tukey s test, one-wy AVA).

7 A mau DX 86 μm ph 5.3 ph 7.4 Serum Zet potentil (mv) B Serum (min) -4 C Intensity (perent) Plsm ph 7.4 ph Size (d. nm) Intensity (perent) Size (d. nm) Intensity (perent) Size (d. nm) Figure S9. (A) The HPLC spetr of DX relesed from FA-PCP@DX t ph 7.4, ph 5.3 or in serum. The spetrum of DX with the onentrtion of 86 μm reorded the stndrd urve of DX. The zet potentil (B) nd size distribution (C) of FA- PCP@DX in PBS solutions t ph 7.4, ph 5.3 nd in serum. Vlues expressed were mens ± SD of 3 independent experiments.

8 Bright field Lyso-trker DAPI Merge min 3 min 2 h 4 h 6 h Figure S1. Intrellulr trffiking of FA-PCP@DX in RHepG2 ells for 6 h, s deteted by Lysotrker-DAPI stining.

9 Reltive mra expression (fold) ** egtive ontrol sira tretment ** ** ABCB1 ABCC1 ABCG2 Figure S11. mra expression level of ABCB1, ABCC1 nd ABCG2 in RHepG2 ells fter tretment of siabcb1, siabcc1 nd siabcg2. The RHepG2 ells were treted with 4 ng/ml of ontrol sira, siabcb1, siabcc1 or siabcg2 respetively for 24 h in FBS-free DMEM. ** represented the sttistil differene of mra expression between negtive ontrol nd sira tretment group t P <.1 level.

10 16 RS (% of Control) ** ** ** Control PCPs (8 nm) FA-PCPs (8 nm) PCPs (2 μm) FA-PCPs (2 μm) PC (2 μm) (min) Figure S12. Intrellulr RS genertion in RHepG2 ells fter tretment of PC solution, PCPs nd FA-PCPs with different onentrtions. ** indited the sttistil differene between tretment group nd ontrol group t P <.1 level. Vlues expressed were mens ± SD of 3 independent experiments. Body weight (g) Control FA-PCP@DX DX (Dy) Figure S13. Body weight of nude mie fter treted with 2.5 mg/kg FA-PCP@DX or DX for 3 dys of tretment, n=3.

11 Tble S1. The ESI-MS nlysis of ompound (1) FA nd (2) FA-EDC. Complexes Theoretil vlue Mesured vlue Belonging to (m/z) (m/z) (m/z) (1) [2M+H] [M+H] [M-C 5 H 7 4 +H 4 ] + (2) [2M] [M+EDC+H 4 ] [M] + Tble S2. In vitro relese kineti models of DX from FA-PCP@DX. Model Eqution R 2 Zero-order Q = t.7523 Serum First-order ln(3.25-q) = t.7877 Higuhi Q = t 1/ Ritger-pepps lnq =.3122lnt Zero-order Q = t.794 ph 7.4 First-order ln(5.518-q) = t.9281 Higuhi Q = t 1/2.914 Ritger-pepps lnq = lnt.9383 Zero-order Q = t.6237 ph 5.3 First-order ln(71.67-q) = t.9172 Higuhi Q = t 1/2.867 Ritger-pepps lnq= lnt.9787

12 Tble S3. Phrmeutil prmeters of nd DX fter iv injetion t n equivlent dose of 4.21 mg DX per kg of mouse body weight. Prmeter FA-PCP@DX DX t ½β (h) AUC -48 h (μg/l*h) C mx (μg/l) Cl (ml/h) t ½β, elimintion phse, hlf-life period of mediine. AUC -48 h, re under urve. C mx, mximum onentrtion observed. Cl, lerne of mediine.