WARNING: SPOILERS for 6x08
This is just my opinion, so Derena fans, please don't bite my head off. I had to let out my feelings.
Dan and Serena have broken up and gotten back together for like a million times. And each time they get back together, they only last 2 or 3 episodes before they decide to break up again. This shows that don't work, as everytime they get back together, 2 or 3 episodes later, something comes up that makes them fight and break up.
Nate handles a Serena episode better than Dan. Nate went through a similar situation wtih Serena in season 3, that Dan went through with Serena in season 1. Lets compare how these guys handled these similar situations.
Dan hooked up with Georgina before they were even officially broken up, hours after Serena told him she cheated on him. When he found out the truth, he helped her, but he broke up with her in the end.
Nate was mad at Serena for all the lying, but was patient with her. Even when he thought she left town with Carter, he patiently waited for her to return. He didn't hook up with Jenny, even if she kept throwing herself at him. And when she told him the whole story, he forgave her and stood by her side instead of breaking up with her. He didn't break up her and was even willing to forgive her for kissing Dan.
Dan only has bad things to say about Serena. In his book, he had good things to say about Blair who was from Serena's world, but he had only bad things to say about Serena. he called her a shallow, self-absorbed party girl. If that wasn't enough, Dan even wrote an expose on her, a year later full of horrible things about her. Not only that, he used her to do it by getting back together with her. I don''t think Dan really loves Serena. Like Serena said in 6x08, "You couldn't say these things about me if you loved me" Dan has always felt insecure in Serena's world and he can't handle Serena being Serena. They've been having disputes about this since 1x02. Dan's a nice guy, but i think he's more suitable with someone from his world who doesn't make him feel insecure and someone with lesser drama/baggage than Serena.
Nate on the other hand loves Serena for who she is. He doesn't judge her like Dan does, and he's always there for her, even when he's mad her. Serena can be herself around Nate. He's also protective of her and deeply cares about her her. He punched Trip for her in 3x12, he gave up his expose on GG which was supposed to be the big story that saved the Spectator to find Serena, he was upset that Serena let Steven kiss her cheek when he thought Steven was cheating on her, he was not happy when he found out that she got back together with Dan, he punched Dan for writting an expose on her in 6x08.
Furthermore, Dan and Serena are step siblings who share a brother. Even if their not siblings by blood, it's still incest, especially if you consider the fact that they share a brother. If Serena and Chuck consider themselves siblings even if her mom was only married to his dad for a few months before he supposedly died, (even after Bart supposedly died) shouldn't Dan and Serena consider themselves siblings, considering his dad was married to her mom for 2 years.
I wish the writers were more faithful to the books. In the books, Nate's the guy Serena's always loved, but in the show, the writers do a 180 and make Dan the love of her life. In the books, Dan and Serena only went on 2 dates in the second book, and then Serena ended it because she found his obsession with her creepy. The writers wrote this show based on the characters in the book, but yet they were only 70% faithful to the first book in the pilot. After the pilot, they completely changed the story, Even if they changed the story, the least they could have done was to be faithful to Serena's character. They not only did a 180 with Derena, they also did a 180 with Serena’s character. I wonder how Cecily, the creator of these characters, feels about this.
In 4x11, Derena agreed that if they ever got back together, it would be their last shot. Now that they've gotten back gotten back together again in 6x06 and broke up again in 6x08 ("Shocker"), that was their final shot, and it didn't work out. It wouldn't make sense for Dan/Serena to get back together after blowing what they agreed was their final shot. Like Serena said "We either sink or swim" and they sank.
I really hope Serenate is endgame. Even if they're not, i'd happy enough with both N and S being single at the end.