Whatever you want to start with.
From the beginning: make it an anthology. Even if the story focuses on Sparda's rebellion, that act affects the entire world across 2000 years of time, not just specific people he's personally related to 2000 years after the fact (his sons) and the people they
meet or make (Nero, et al).
DMC1 centers around Dante tackling Sparda's legacy and reforming a full-demon (Trish) while in pursuit of justice/vengeance. Maybe this time Trish fakes as if she's actually Eva returned from the dead, so the deception hits Dante harder than if she just busted his door down and electrocuted him like it's something to do. After Dante defeats Mundus and avenges his mother and brother, his arc is over. At best, a new game would focus on Trish and what it's like for a full-demon to gain a conscience after only being a tool for evil, thereby indirectly clueing us in on what Sparda might have gone through 2000 years ago when he first rebelled against Mundus himself. Funnily enough, one of Mundus's lines of "Sparda blood [spoiling] over the ages" could suggest that Dante is a distant
descendant of Sparda instead of direct because of Mundus denoting "the ages" as a reason, not just that Sparda mated with a human woman once and ruined the bloodline by making a single pair of half-breeds.
DMC2 was better without Dante in it so it'd be Lucia-centric, concerning her self-identity with regards to being a tool of Arius's creation when she thought she belonged to a part-demonic bloodline and pagan culture. She could still be a clone of some undisclosed woman, but Lucia's arc completes with Matier confirming that their bonds are deep even without blood relation and that her cultural ties to Dumary matter more than her origins as Arius's Secretary. Matier would probably still have a story about Sparda or it'd be in the background lore, but it'd be more important to establish Argosax as an outlier in Dumary's worship of demons and suggest that the pantheons of gods we know of are potentially demons in different guises with their own morals, goals, and whatnot, instead
of a chaotically evil hivemind that only shows traits of nobility and loyalty whenever someone feels like writing it in.
DMC3 was also better without Dante in it because he was a poorly done protagonist and Lady had more stakes and a personal connection to the villain, so we'd be checking in on someone descended from the bloodline of a mortal/holy priestess, because her father is deluded over the priestess's history and her legacy. Arkham was clearly picking and choosing what parts of lore to go with, i.e. the Priestess was "sacrificed" so that Sparda could "become a legend", and he totally glossed over the fact that Sparda lived in the human world quietly and wasn't bleeding women out on altars just for kicks and relevancy.
DMC4 is ^drumroll*
better without Dante in it! So, Nero-centric without any bloodline connection to Sparda, or an otherwise negligible one, like, 1/16th of his genes or less. The most notable form of Sparda's effects on Fortuna is the religious cult that still worships the guy. Have it be that the general populace is disillusioned about Sparda's presence and they only go to church out of habit or during special occasions, which triggers Sanctus's plot of "The Savior" and Agnus's cynical monologue about how humans come closer to believing in God only when they experience Hell. Nero is reluctantly sided with the Order because he agrees with their ideals of "killing demons" and he wants to make the town a safer place to live in, but he couldn't care less about their focus on "the Savior"/Sparda specifically. It could even be a personal dislike because the town suffered casualties from a demon invasion when Nero was a child, so he wants to restore his hometown's glory and prove that people can attain power and protect themselves without relying on God, as Sparda wasn't there to save the town when it was ravaged decades prior. Then he loses the use of his arm and he wrestles with whether that constitutes some type of divine punishment.
Barring making it an anthology focused on different characters around the world, if I had to actually include all the characters in the games as we've seen them and edit their existing stories, I can probably wiggle some other plot out of them if not link to posts where I've talked about alternate character arcs.
What's the reason they give for why he is always getting rid of his devil arm? Because he's not the type of man to get attached to possessions. In the drama CD, why doesn't he stop Trish from leaving? Because he's not the kind of person who understands the feelings of others.
the reason they gave? I thought he was constantly selling off his weapons to pay penance to Enzo because he considered himself responsible for the missing arm and tries to make it up to him even when Lady thinks Enzo is abusing that connection. Same with him putting his money into the bank accounts of Grue's daughters to make up for the fact that he indirectly got their dad killed-- that would be enough to justify his debt in a twisted utilitarian(?) perspective (he can get money back, not people's lives, so being in debt and suffering temporary hits to his own quality of life is preferable in comparison to getting allies maimed or killed)-- then the anime torpedoed sensibility in the nuts and portrayed Dante as incompetent with his money and his own job, to where he routinely causes massive collateral damage in the name of coolness.
Oh well, characterization marches on, I guess. I'll just be amused that by these writers' own logic, if Dante's "reason for fighting" is Vergil/Urizen/whatever and he "cares" enough about his brother to still fly into a rage at the mention of him, they just invalidated the whole of episode 10 of the anime and exposed Dante as OOC x 20 by having him call Modeus "pathetic" for his willingness to drop his pacifism in the name of avenging his recently murdered brother. Dante really had no room to talk there given he's much worse.