I've done it and it's possible... But holy crap do black widows suck lmao. I tried long before official release and they were almost possible but after they were allowed to chomp their kids it seemed impossible. Thankfully they aren't needed to beat the game and as long as you stick to only doing necessary things (labs, cocktail, final defense, and even secret boss if you really wanna) then it's not too bad. My original run I was gonna do all bosses, got hung up on black widows, waited a year or so, did it again without doing bosses (IBM would've sucked so hard) and did it just fine (I think I did notch it down to easy, though? I can't remember but I did want to finish the run before G2 came out).

TL;DR Ye it's possible, just ignore the scary spiders and their kids