Syrian government forces closed the only road leading into and out of rebel-held parts of the northern city of Aleppo on Sunday, besieging hundreds of thousands of people and giving President Bashar al-Assad’s forces one of their biggest successes since the conflict began in 2011.

Sunday’s push raised fears among the city’s civilian population of a humanitarian crisis as many worried that food and medicine will run out in Aleppo within a short time.

The siege marks the biggest victory for the government in Aleppo since rebels captured parts of the city in summer 2012. Aleppo, Syria’s former commercial center and the country’s largest city, has been divided and contested since then.

Aleppo and its suburbs have seen intense fighting in recent months, with Syrian troops and their allies advancing with the aid of Russian airstrikes. Earlier this year, the government launched a large-scale offensive that captured much of the city’s northern outskirts.

The capture of the road came as Russia and the United States, which support rival parties in the conflict, are negotiating a possible military partnership over Syria. Both countries have been trying to end the conflict.

An eventual government victory in Aleppo would be a major turning point in favor of Assad.

The Britain-based Syrian Observatory for Human Rights said government forces and members of Lebanon’s Hezbollah group reached Castello Road early Sunday, closing it and raising fears of a humanitarian crisis.

“Aleppo is under full ground siege after the regime took some points on the road,” Aleppo-based activist Bahaa al-Halaby said by telephone. He added that as of Sunday, food and medical supplies will not be able to reach rebel-held parts of the city and seriously wounded people will not be taken for treatment in other parts of northern Syria or Turkey.

The Observatory said that 16 militants were killed in Sunday’s fighting and that

government forces are still pushing to gain more ground around Castello Road to make it difficult for any rebel counteroffensive to reopen the route into the city.

The conflict has killed more than a quarter-million people, created Europe’s biggest refugee crisis since World War II and allowed the Islamic State militant group to carve out its own territory across parts of Syria and neighboring Iraq.

The United Nations warned this month that nearly 300,000 people rely on Castello Road for travel, food and medicine.

The siege on rebel-held parts of the city came hours after mysterious explosions rocked a sprawling government military facility outside the town of Safira, just south of Aleppo.

The Observatory said that the cause of the explosions was not clear but that they killed at least 10 people and caused heavy damage.