*2.1. Materials*

SA (200–500 Pa·s) was purchased from Shanghai Taitan Technology Co., Ltd., Shanghai, China, anhydrous calcium chloride (CaCl2) was purchased from Shanghai Lingfeng Chemical Reagent Co., Ltd., Shanghai, China and Polosham 188 (F-188) was purchased from Shaanxi

Zhengyi Pharmaceutical Accessories Co., Ltd. Carbon support copper mesh (230 mesh) and phosphotungstic acid were obtained from Beijing Zhongjing Keyi Technology Co., Ltd., Beijing, China. 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate (Dil, cell membrane green fluorescent probe), Hoechst 33342, 4% paraformaldehyde fix solution, antifade mounting medium and Cell Counting Kit-8 (CCK-8), were all purchased from Biyuntian Biotechnology Co., Ltd., (sShanghai, China) 5(6)-aminofluorescein was bought from Nanjing Xinfan Biotechnology Co., Ltd., Nanjing, China. Polycarbonate film was bought from Whatman Company, City, UK. Dialysis bag (Cut-off molecular weight = 3500Da) was obtained from United States for carbonization. Fetal bovine serum (FBS), RPMI 1640 medium, and DMEM medium were ordered from the Shanghai Chenyi Biotechnology Company, Shanghai, China. Trypsin and penicillin-streptomycin were purchased Yingjie Jieji (Shanghai) Trading Co., Ltd., Shanghai, China.

### *2.2. Cells and Animals*

RAW264.7 cells (mice macrophages) and HEK-293 cells (normal human embryonic kidney cells) were bought from the Shanghai Cell Bank of the Chinese Academy of Sciences, Shanghai, China, and cultured with DMEM complete medium. SMMC-7721 cells (human liver cancer cells) and NB4 cells (APL cells) were obtained from Shanghai Jihe Biotechnology Co., Ltd., Shanghai, China and cultured with RPMI 1640 complete medium. Culture of the cells was performed in an incubator kept at 5% CO2 and 37 ◦C. The male BALB/c nude mice (SCXK 2017-0005) were obtained from Shanghai Slack Laboratory Animals Co., Ltd., Shanghai, China and kept in the Specific Pathogen Free (SPF) animal room of School of Pharmacy, Shanghai Jiao Tong University. Guidelines for care and use of laboratory animals of Shanghai Jiao Tong University were used to perform animal studies and these studies were duly approved by the animal ethics committee of Shanghai Jiao Tong University (No: A2019046, Date: 5 July 2019).

### *2.3. Preparation of SANs*

SANs were prepared by the ion crosslinking method. In brief, 1.5 mL of 2 mg/mL CaCl2 was slowly added into 10 mL of 0.3 mg/mL SA (pH = 5) under stirring. After sonication for 5 min at 250 W, 0.1 mL of 10 mg/mL F-188 was added and then stirred for 30 min. To obtain SANs, 0.2 mL of 8 mg/mL ATO was added and stirred for other 30 min.

## *2.4. Preparation of RBCM*

RBCM was extracted by hypotonic rupture method. In brief, whole blood of SD rats (bought from Shanghai Jiesijie Experimental Animal Co., Ltd., Shanghai, China) was collected through abdominal aorta. The blood was centrifuged (2000 rpm, 5 min, 4 ◦C), to obtain red blood cells (RBCs), and then washed with 1× phosphate buffer saline (1× PBS) for 3 times. To collect RBCM, 900 μL EDTA (0.2 mM) was added to disrupt the RBCs, followed by centrifugation (13,200 rpm, 10 min, 4 ◦C), and the above steps were repeated until the supernatant turned colorless. The obtained RBCM was resuspended in EDTA, and then stored in −80 ◦C refrigerator.

## *2.5. Preparation of RSANs*

The prepared RBCM was sonicated at 250 W for 3 min to obtain RVs, and then sequentially extruded through polycarbonate films of 800 nm, 400 nm, and 200 nm by LF-50 extruder (Avestin Inc, agented by Shanghai Narujie Biotechnology Co., LTD, Shanghai, China) for at least 15 times respectively. The solutions of RVs and SANs were mixed at a ratio of 1:8(*v*/*v*). The prepared mixture was then extruded through polycarbonate films of 400 nm and 200 nm at least ten times, respectively, to obtain RSANs.

### *2.6. Characterization and Stability Test*

The particle size and polydispersity index (PDI) of SANs and RSANs were determined by Malvern Zetasizer (He-Ne, 4.0 Mw, λo = 633 nm, Marvin instruments Ltd., Marvin, United Kingdom. The stability test was investigated simultaneously. The particle size and PDI of SANs and RSANs were measured for 15 days consecutively at both 4 ◦C and 37 ◦C.
