Mathews ran for 98 yards and Weddle picked off Matt Cassel on the Chiefs' final drive with less than 2 minutes remaining to wrap up the win for the Chargers (2-1).
Philip Rivers went 24-of-38 through the air for 266 yards, overcoming a pair of interceptions in San Diego's victory.
Cassel managed 176 yards and two touchdowns behind center for Kansas City.
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