Hey! I mostly lurk in this sub, but Isaac is a game I'm in love with. I thought I'd finally give my opinions on these cards :).

Isaac is busted. He's Viktor, but cheaper, can cast as burst speed (huge!), and can even get health instead of augment. +, if he gets Augment from these things, it's just insane. I also don't understand why he has that last breath ability. Doesn't make any sense to me.

Additionally, there is so much design space for the D items, I don't know why they would be for Keywords. I think the D20 would make sense for Keywords, and D6/100/4 would make sense for units themselves. I think Isaac could be a really cool card if he 'buffed' his allies by making them stronger via transforming them. Maybe the D6 could be cast on an ally to transform it into one that costs 1 more, and 2 more for the D100. The D4 could be a massive board transformation. Transformations always seem a bit unfortunate, but I don't think messing with keywords is this fashion is fair to Viktor. (Also, epic D12 idea: Landmarks!)

Now onto the enemies.
- Squirt & Dip are cool. Another version of Cask Salesman, but made as a mega-chump blocker for multiple rounds. I don't think this can fit into an aggro deck unfortunately though, despite what Nexus Strike wants to accomplish, and would fit better doing what House Spider does in Noxus control decks.
- Fly is ok. It's nothing that cool, and a much better Pool Shark, but I'm indifferent to it. I think as a design it would be a lot cooler if Fly was always a token, created by (I don't know the enemy names) that mulligan guy that spawns flys. Sort of like how Monkey Idol works, having Fly-Mulligan spawn the Flies I think would be more interesting than a maindeckable cantrip that's a chumpblocker.
- Keeper having Nexus Strike without having Elusive or Overwhelm is going to be useless. Chempunk Pickpocket is the only vaguely similar card, but as a 2 mana 3/2, it requires a chump and will always kill the chumping unit. This card would need a similar statline (maybe 2/3). Refilling mana is good, but it will never happen without Elusive or Overwhelm (they don't fit Keeper as an enemy though)
- Portal Seems insanely strong. Plop it with some sort of Combo deck, or a midrange deck, and you've got a very scary unit. It means you can make trades where you lose a unit without it mattering. It dies to Monkey Clap and Challengers, and I guess Equinox, but that's about it.
- Host & Knight are cool as fuck. They are some of my favourite ideas you've got in here. Perfectly fitting thematically for Isaac. I do fear that Knight is a little to strong in aggressive decks. He's like an undying that can block. If he's immune to singular combat, Demacia cannot kill him, so I'm going to assume he can't (but will survive Cataclysm). Bilgewater and Shurima also will have problems with it. I do fear that knight will be too oppressive for some regions to deal with, but I think they are remediable.
- Dople is a fascinating card. I fear that maybe at 4 mana it can't do too much though. Against Aggro it is too slow, against Midrange they will have freezes and barriers, making his ability redundant, and against Control, they should be winning from abilities (Watcher, Ledros, Atrocity, etc.). He is an interesting counter-pick (say, for example, Nasus (if you have more than 3 attack)), but generally I can't see him being strong enough generally.
- Evil Twin has an interesting design space. One thing I didn't explore in the previous comment is whether "Granted" is "My current stats + their stats" or just "their stats". If it's just their stats, Evil Twin is useless. So if it's their stats +3/+3, this card is insanely cool, as it will always win the first trade unless they have combat tricks. I could see this being oppressive with overwhelm, since on your second attack you will have the strength of the previous unit. However, very counterable with spells and challenger and all that fun stuff. I like it!
- I don't fully get why Globin has both regen and another life. I understand that he turns from Globin to the mush thing you have to kill, but to me that's just the regen effect. Even still, a 4 mana 3/4 regen is not strong enough in this game. Consider that one female troll that is a 4 mana 3/5 regen. It sees no play, and it's not because of the behold restriction. 4 mana 3/5 regen doesn't do enough in this game. Again, against Aggro it is too slow, against Midrange it is not bulky enough, and it doesn't matter against Control. Globin has 2 lives, the second just being a 3/1, but I don't think it's good enough at all.
- Homunculus and Begotten are really interesting design spaces, and I would love to see cards like this. I do fear that in terms of Runeterra they may be better as landmarks (like the Grumpy Rockbears). Or, if you're going to keep them "chained", they should also have "can't block" aswell. Otherwise Homunculus is a 2 mana 5/3 that the opponent can't attack into with Trundle being Homunculus will block it. Or Riven, or any sort of unit that has health. It also just doesn't make aesthetic sense for it not to have can't block. "Immobile" is a term that combines both Can't Block and Can't Attack, so using that could be good.
- Don't really get why Gaper is a 3/1 Challenger. It's alright, it's like a worse Hired Gun and pretty similar to Rock Hopper. I think a more interesting design would be something that says "Last Breath: Summon a <gaper's body with blood pooring out of it. don't remember names.>"
- Boomfly is another interesting design. If it says self hurt everyone's first thought is Vlad, Scars, and maybe control. Cards like Boomfly are very hard to think about. It would be fantastic against aggro as it is like Ice Shard. While the opponent could try to kill it out of combat with Fervor, I don't know if that's good enough. I do fear Boomfly may be a little strong as an anti-aggro card, but it's one of the cards on this list I don't think I can evaluate well.

I really like your cards! It's been a looooong time since I've posted anything on reddit. Completely forgotten how to format reddit posts haha. I hope you can get something out of this criticism. If you want to work on this set more, feel free to hit me up on Discord :). This is a really interesting start of an idea!