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Messi scored a hat-trick and set up Neymar as Barca claimed a convincing victory at Camp Nou on Wednesday.
In an eventful encounter, City had goalkeeper Claudio Bravo sent off, Jeremy Mathieu saw red for Barca and Neymar missed a penalty.
Nolito had no doubt as to who was decisive in the Group C clash.
"Messi is the best player in the world so he makes the difference," he said, via the club's website.
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"When he gets the ball he always does something, a goal or an assist."
City were only trailing 1-0 when Bravo was sent off, and Barca took advantage to secure a comfortable three points.
Nolito felt the scoreline was harsh on his team, saying: "We played well in the first half, we had our chances but in the second half we were unlucky.
"This is football, we need to keep going. Today was a very hard game against Barca, but we did not deserve to lose 4-0."
Pep Guardiola's men are now winless in four in all competitions ahead of hosting Southampton in the Premier League on Sunday.