Alternate between Nature and Stone defenders. Use Aqua on key locations (triple intersections, enter/exit points). Use a maximum of 3 Aqua defenders.
On entrances, you want Poison Nature and Lava Stone defenders. On exits, Nulifier Nature and Critical Stone defenders. All Aqua defenders are upgraded to Freeze.

You don't have to research Root Nature, the Triple Aqua Triple Aqua, Blast Aqua and Zap Stone. Use that research money for upgrading your Defenders.

At the begin, you want to fill the battlefield with Defenders. Start from entrances, move to exits then the go-between space. Only then start upgrading and researching.

First upgrade can be either Freeze Aqua or Critical Stone. I usually go for the latter one. On higher levels, you want to first upgrade your Exit Stone Defender to Critical, then the Exit Aqua to Freeze. Otherwise, Twisters will pass through your Exit Guardians without taking damage (Freeze and pure Stone can't hit them. On the other hand, pure Aqua and Critical Stone can).
After that, get the other upgrade (Freeze if you started Critical and vice versa).


Third upgrade is Poison Nature, then Lava Stone and, finally, Nulify Nature.

The upgrade sequence goes as this:
First, all defenders to Rank 1. Then, you pick the defenders you want to Specialize and get them to Rank 2, then pick Specialization class. Order varies from map to map, but my usual setup is:

Exit Stone to Critical, Exit Aqua to Freeze, other Aqua to Freeze, Entrance Nature to Poison, other Stone to Critical, Exit Nature to Purify, other Stone to Lava, other Nature to Purify.
This way, I first ensure low HP enemies die before the Exit, Armor Gingulata die from the Critical and there is spread out Freeze over the map for longer battle times. Then, I try to eliminate more enemies (especially Stealth Rogues) with the poison, increase damage throught the map, ensure homing missiles (Exit Purify) for the event some low enemy passes Freeze and Critical. Then just add more Damage over Time with Lava and more Nulify to burn enemies abilities.

DoT is OP but dont overdo it. Make sure the enemies' Burn from the first Lava Stone has expired, before your second Lava Stone starts firing off and setting them again on DoT. So, if you decide to put 3 Stone Defenders in a straight line, go for Lava-Critical-Lana, rather than Lava-Lava-Critical. ;)

Hope it helps!