Nightmare turns into a more dangerous, yet vulnerable form after you hit the arena switches that solidify it. According to its Enemy File, these are justified; those things allow it to be restrained and controlled in the first place, ensuring that it will do what its maker wanted. These restrictions also make sense from another perspective; considering how powerful and adaptive Nightmare is while it's vulnerable, it's understandable for Mundus to actually prefer Nightmare in its "battle" mode because its default black goo form doesn't really do anything much in comparison when it comes to combat effectiveness. After all, Nightmare is one of Mundus's servants who are supposed to defeat Dante.
Nightmare's swallow attackworking only once against Dante might have a meaning beyond gameplay; the dimension is stated to be a result of Dante's underlying mental trauma from all his demon-hunting. The bosses that appear are also Killed Off for Real by the time the fight happens, so Dante is facing his demons in the form of his most recent traumas (a.k.a. the most recent bosses). The attack only works once for that fight because Dante is overcoming that particular trauma.
Whether this allusion was an intentional Shout-Out to Classical Mythology or not is unknown, but the Nobodies are among the most difficult and/or annoying enemies to deal with, and they are notorious for their exploding eyeballs. What's the alias Odysseus goes by in the The Odyssey when he and his crew are up against the Cyclops and stab it in the eye? "Nohbdy", which is coincidentally pronounced like, and has the same meaning as "Nobody" in English, albeit the game's Nobodies differ in personality because they are brutish rather than clever.
During the first phase of the boss fight in Mission 22, Dante cannot use Holy Waters under the In-Universe explanation that those don't work against Mundus. But strangely enough, they can be used in his second phase within that same mission. From a gameplay perspective, the inability to use Holy Waters in the first phase can be justified because Mundus is too far away. On the other hand, the ability to use Holy Waters in the second phase can be justified because Mundus is now within range, and was already weakened at that point.
The Prophecy regarding Mundus's downfall ("Pluto shall come on the promised date and separate heaven and earth. One with black wings of treachery shall come and stand in Pluto's way.") is mentioned by a book in the castle's library. The "one with black wings of treachery" clearly refers to Sparda, who has black bat-like wings in his demon form, and has betrayed the demonkind. It goes along with the recurring narrated backstory of the series which mentions Sparda sealing Mundus in the Demon World. However, that same passage can also be referring to Dante, interpreted as both a foreshadowing to the Final Boss battle, and the son following his father's footsteps; Dante also takes on the black-winged demon form of Sparda via his namesake sword, then stands in Mundus's way by sending him back to the Demon World again.
At some point, Mallet Island was filled with humans keeping the place up and running. By the time Dante arrives, any traces of human activity are gone, not even bloodstains or bodies are left behind except for maybe one or two outside of the castle at best. Naturally, the demons very likely killed everyone on the island, but what happened then? Given how demons in fiction tend to act, there's a possibility that the other humans were eaten.
In the open courtyard near the Colosseum, you can hear sounds of crickets and several animalistic growls and noises. Particularly, there's also a noise that sounds close to that of a monkey, which sounds eerily like evil laughter. And since the island doesn't show any signs of life except for Dante and the demons, are those truly animals you're hearing?
