After platinuming this great game I have some thoughts.
Boss rush: Prioritize hull and regen over harpoon charges.
Going into the final boss with one or two higher regen than hull and zero points in harpoon.
No upgrade create run: Skip the parasite boss
Also skip the chain gang you can get the upper harpoon open the door and leave. Man do i wish i had known that.
Because your health will regen in this mode the only really difficult boss is The Experiment because he has an absurd amount of health.
The trick is like dark souls, stay under his tail and he cant aim at you with his turret. That fight will take forever.
The final boss is all about dodging.
Hardcore run. The hardest boss for me was the octopus and the final boss.
The hardest part of hardcore is getting to the triple harpoon upgrade. After that you can shred every other boss in under 20 seconds.
I did it in this order: The Worm, The Fathers, The False Light, The Chain Gang skip, the Defiler, The Tranquil, The Parasite, The Forgotten One, The Heart of The City, The Experiment, The Devs, Final Boss part 1 and 2
If there is any more questions I did stream 99% of this on twitch under the same name. But I can always answer more here too