Five years ago, an unexplained accident results in the spread of billions of incomplete microscopic nanites into Earth's atmosphere.
Tiring of Providence's control over his life and poor treatment of him, Rex sneaks out of their headquarters with his EVO chimpanzee friend Bobo and meets Noah Nixon, an ordinary teenage boy whom he befriends.
Deeming the spread of Dr.Meechum's control too dangerous to contain, White Knight initiates Bleach Protocol, ordering for a nuclear weapon to be detonated on the Manhattan Bridge to kill Meechum and the infected.
Hearing a strange noise at night, Rex encounters Circe under attack by a huge EVO sea monster.
Van Kleiss claims he has come to deliver a speech to the United Nations delegates on Abysus' behalf, but Providence remains suspicious of him.
They claim that the only way to reverse the process is via a machine built by Van Kleiss, and Rex reluctantly agrees to help them after Dr. Holiday mentions the risks of allowing the corruption of Abysus to continue.
Van Kleiss then discovers that Rex's nanites have given him the ability to turn living things into EVOs, and he proceeds to mutate all of the Keep's crew, including Captain Calan.
Rex is sent on an undercover mission to spy on Van Kleiss and the Pack, including his siren-like sweetheart Circe, who travel to the Bug Jar planning to strike a deal with its leader, NoFace.
They soon discover that his EVO cure is a ruse, and Moses is in fact collecting dangerous E.V.O.s to sell them to the highest bidder, using a device to supercharge their nanites.
When Alpha became self-aware and attempted to assimilate living things, Caesar developed a device to send it to an empty dimension where it would do no more harm.
Alpha continues to grow in strength by assimilating more living things, until Rex, Ben, and White Knight confront it in the Bug Jar, where it has absorbed all of the resident EVOs.
Rex, Six, and Bobo travel to Cairo, Egypt, where Dr. Holiday is investigating a recently uncovered ancient tomb containing hieroglyphs seemingly depicting nanites.
Gharun Set escapes from his tomb and reactivates a series of technologically advanced pyramids buried underground, which rise up across Cairo.
Gharun Set also destroys the Great Sphinx of Giza, revealed to be a tomb for an enormous two-headed cat EVO which he restores to life.
Caesar states that he is in fact in charge of the new Nanite Project, and is attempting to restore Dr. Gabriel Rylander to life in the same manner as Van Kleiss.
Van Kleiss is being pursued by a mysterious force, which he is convinced is an "antibody" of spacetime which is attempting to destroy him for being a violation of the laws of physics.
Van Kleiss is brought to the Colosseum in Ancient Rome, where he wins the favor of Emperor Septimius Severus, who worships him as a god.
Van Kleiss is able to repair his machine and escapes once again as the entity pursues him, jumping across the eras in a desperate effort to make it home.
Angry at the flawed results of the experiment, the Consortium take out their anger on Rex, until Providence suddenly intervenes, with White Knight having returned as leader.
After contemplating this, Rex finally confronts the Consortium, just as they are attempting to redo the experiment to gain the full power of the Meta-Nanites.
The Consortium restart the process, but Van Kleiss betrays them, revealing that he has retained his sanity and has always intended the power of the Meta-Nanites for himself; he strongly implies that he killed Rex's parents after they tried to stop him.