## 2 Materials and Methods  
### Materials  
_DL_-lactide (LA), glycolide (GA), monomethoxy poly(ethylene glycol) (mPEG, \(M_{n}\) = 550), pentaerythnitol (PTOL), succininic anhydride (SA), 4-(dimethylamino) pyridine (DMAP), 1,3-dicyclohexylacarbodimide (DCC), and stannous octoate (Sn(Oct)\({}_{2}\)) were purchased from Sigma Co., Ltd. Indomethacin (IMC) (99% purity) was purchased from Aladdin Chemistry Co. Ltd. Gestodene (GSD) and ethinyl estradiol (EE) (microcrystalline powder, 99% purity) were obtained from Beijing Zizhu Pharmaceutical Co., Ltd. HPLC-grade methanol was purchased from China National Medicines Co. Ltd. Ultrapure water was prepared by a Milli-Q50 SP Reagent Water System (Millipore Corporation, MA, USA) for the preparation of samples. Other reagents were of analytical grade. Preparation of Four-Arm Star-shaped poly(D,L-lactic-co-glycolic acid)-b-methoxy poly(ethylene glycol) (4 sPLGA-mPEG) Block Copolymers  
The four-arm star-shaped poly(D,L-lactic-co-glycolic acid)-\(b\)-methoxy poly(ethylene glycol) (4 sPLGA-mPEG) block copolymer was synthesized by our previous reports with minor modifications, as shown in Figure 1a [44]. The 4 sPLGA-mPEG block copolymer with LA/GA mol ratio of 9 was designated as CP-1, a block copolymer with LA/GA mol ratio of 3 was designated as CP-2, and block copolymer with LA/GA mol ratio of 1 was designated as CP-3. The block length of each arm for all block copolymers is 1320-550. The four-arm poly(D,L-lactic-co-glycolic acid) (4 sPLGA) copolymer was prepared as follows, take CP-1 copolymer as an example. Firstly, pentaerythnitol (0.0015 mol, 0.204 g), LA (0.0505 mol, 7.27 g), and GA (0.0058 mol, 0.65 g) were dried under dry nitrogen atmosphere and stirred at 100 \({}^{\circ}\)C for 2 h in a three-necked flask under vacuum. Then the temperature was increased to 160 \({}^{\circ}\)C for 1 h, Sn(Oct)\({}_{2}\) (0.0056 g) was added into the melt of reactant and stirred for 6 h. After reaction, the temperature was lowered to room temperature and acetone was added into the flask and  
Figure 1: Schematic illustration of multi-drug (Ethinylestradiol, Gestodene, and Indomethacin) loaded four-arm star-shaped poly(D,L-lactic-co-glycolic acid)-\(b\)-methoxy poly(ethylene glycol) (4 sPLGA-mPEG) block copolymer hydrogels as vaginal hydrogels for contraception. Drugs were involved in block copolymer solution, then the solution was injected into the Sprague-Dawley (SD) rat vagina, multi-drug loaded hydrogels was formed with the help of body temperature. precipitated with Millipore water. This purification process was repeated twice, and the product was dried by a freezing-drying method to obtain 4 sPLGA copolymer. Secondly, the carboxylic mPEG was prepared. The mPEG-550 (0.006 mol, 3.30 g) was dissolved in a 200 mL chloroform in a three-necked flask, SA (0.0075 mol, 0.75 g) and DMAP (0.0075 mol, 0.915 g) were added into and stirred at room temperature for 24 h. Then, chloroform was evaporated under reduced pressure, and the residue was slowly added to saturated sodium bicarbonate solution, then extracted with ethyl acetate, the product was dried by using a freezing-drying method to obtain carboxylic mPEG. Finally, the prepared 4 sPLGA copolymer, carboxylic mPEG, and DCC (0.006 mol, 1.238 g) were dissolved in 200 mL dichloromethane in a three-necked flask, stirred at room temperature for 1 h, then DMAP (0.003 mol, 0.337 g) was added to the reaction and stirred for 36 h at room temperature. The dicylohexylurea as DCC hydrates was removed by suction, and then the reactant was added into diethyl ether and precipitated at 4 \({}^{\circ}\)C for 24 h, this purification process was repeated twice to obtain 4 sPLGA-mPEG block copolymer. A proton nuclear magnetic resonance (\({}^{1}\)H NMR) spectrometer was used to characterize the chemical composition of the prepared four-arm star-shaped block copolymers.