The Citizens have lost all five of their previous encounters against fellow English sides in continental competition, including both legs of their quarter-final with Liverpool last season and last week's first leg against Spurs.
Having won 23 of their 25 home matches in all competitions this season, however, City will be confident that they can overturn the 1-0 deficit inside 90 minutes at the Etihad Stadium on Wednesday night.
Ahead of the all-Premier League showdown, Sports Mole looks at how Pep Guardiola may set out his side.
De Bruyne appears certain to return on Wednesday evening, though Sane has been overlooked against the big sides of late and may have to settle for a substitute appearance once again.
Of more concern to Guardiola will be the fitness of key man Fernandinho, who missed the 3-1 win over Crystal Palace at the weekend with a muscle injury, though he is expected to be OK to return here.
Bernardo Silva returned to action with 25 minutes at Selhurst Park, meanwhile, and is in contention to start in the frontline.
Elsewhere, Sergio Aguero is likely to get the nod over Gabriel Jesus, and Zinchenko is in contention to replace Fabian Delph at left-back, assuming Guardiola does not fancy taking a risk on a not-yet-fully-fit Benjamin Mendy.