Hard as nails
Finish the game in Difficult mode
Finish the game in Extreme mode
You can start out on Extreme mode, which requires you to thoroughly master the game, as well as have a pretty big focus on the secondary missions (which you need to do for an achievement anyway) for experience, and also to loot boxes and scrap piles (which you also need to do) for enough scraps to upgrade your items, and create ammo and healing items to make your trek through Extreme, less extreme.
Recommended Skills (I call this Sapper Spec)
Max Out Tough Skin (Combat) and First Aid (Renegade)
Upgrade Science of Evasion twice (Combat)
Work on Renegade until the Technomancer tree unlocks
>Max Subtility and Vicious as early as possible, as well as at least Assassin 1
Once Technomancy unlocks, upgrade Empowering Fluid twice.
Finish upgrading the Renegade tree for Specialist, or at least get Combat Injections 3
Toss any other points into Weapons Mastery (Combat) and whatever else you want.
Combat - 9, Renegade - 36, Technomancy - 3*
*I wasted a point on Stable Shield.
Skills and Reputation:
Invest in +xp % skills to increase your leveling rate and thus the number of skills you can unlock. You can upgrade Handiwork if you want, although with Good alignment it becomes cheaper to buy ammo from a merchant.
As for your reputation; you can either refrain from harvesting serum from enemies to reach good and excellent reputation (recommended) or harvest all enemies for a boost in serum and a decline into the Terrible reputation. If you help everyone you can, remain nice, and spare your enemies, you will get a discount at merchants (50%!) and eventually a boost in your companions hp and damage (also 50%!), which both greatly outway the Terrible rewards in my opinion.
Weapons and Armor:
Weapon: Bone tip and heavy grip
Armor: All Technowarrior
The most important skills you have are sand throw and wound. The first isn't upgraded via weapons, but you can increase your chance of wounding by 15% by giving your weapon a bone tip (or 5-10% with a lesser tip). You also want to reduce damage, while increasing your damage, which you can do with the heavy grip.
As for the armor, you will want to start off upgrading to Reinforced Leather, then Metal, and finally Technowarrior as they become available. This will reduce all incoming damage substantially, and with the abundance of health items, and lack of any need for fluid regeneration using this spec, damage resistance is what you will need most.
to sneak up on unsuspecting enemies and thin their numbers prior to starting battles. In some cases you can even stealth knockout (Assassin 1 skill required) all of the enemies in a group. This aspect of the build doesn't come in hand until Chapter 2 starts, however.
Use sand throw! I kept sand throw bound to
for the duration of the game, as it is fantastic in combat. Of course, it can't be used against enemies with visors or goggles, but when enemies are blinded (Technomancers included!), they have a chance to hit their allies for huge damage (compared to you) and are also unable to accurately hit you, or block your attacks.
Wound! In a similar fashion to sand throw, wounding will greatly weaken an opponent to the point where the move at a fraction of their speed, they're unable to block your attacks, and you will be able to do more damage to them. While critical hits can do huge damage in a single blow, focusing on increasing your wound chance % allows you to do more damage in the long term, and also allows you to shoot enemies with your nail gun (high wound chance) to basically crowd control multiple enemies with wounds.
Chapter 1 Boss tips:
Try and save as many nail gun nails as possible as you make your way from the prison to the train station as they do considerable damage to the boss while his shield is down. Once the fight starts, be sure to utilize your blind ability to quickly take out the other enemies, and note that blind also works on the boss, though it doesn't do much. Once it's just you, him and Innocence, Innocence should be targeted for a majority of the fight, allowing you to keep whacking the boss in the back for bonus damage and a quick finish.
Chapter 3 Boss Worm:
After spying on Wisdom, and before talking to the General, make yourself a ton of healing syringes as the boss worm fight involves taking tons of damage and is immediately followed by another boss fight, though he's basically just an upgraded technomancer - quite a pushover.