I think if there was multi-million dollar budget the Gen-1 Insight could be modded up to ~100 MPG... but it will always increasingly expensive to keep squeezing 1 more after 1 more after 1 more ... etc... and the nut behind the wheel is always the biggest unknown.
In addition to what was already listed ... I would also include in a unlimited budget Insight ...
waste heat heat recovery radiator and exhaust ... more than 50% of the energy content of every gallon of gasoline is currently being thrown away.
Body panel exchange for photovoltaic panels of the same or better aerodynamics , and the same or lighter weight.
Install photovoltaic tinted glass ... will reduce AC usage in summer ... and will generate electrical power instead of just a regular dye type of tinting.
Meredith effect jet thrust from the waste heat we can't recover and from the exhaust gas pressure.
Include a completed 2nd clutch project 4 graduate engineering students at the university of Michigan worked on about ~6 years ago now.
Efficiency driving map programs... for the most efficient route.
Force the ICE to always stay in it's highest efficiency lean burn state ... power to keep acceleration and such would come from the larger IMA motor already posted previously.
A real time display of vehicle operating efficiency ... ideally with the ability to switch to view the components of that efficiency.
Down size the gasoline tank ... if we are getting ~100 MPG 3 or 4 gallons should be plenty.
A waste heat recovery system for an improved climate control system ... in the summer we have a mini solar oven collecting heat with the windows up ... what can't be directly converted via photovoltaic systems should be converted other ways indirectly.
Include exercise pedal generators ... every tiny bits helps ... and on long road trips the physical activity would be welcome to some ... like me.
Of course LED lights all around.
Front wheel skirts.
Seal the engine compartment ... we want all the heated air to go the way we want it in controlled waste heat recovery systems ... not just get thrown away.
I think that is it off the top of my head ... for my own short list ... in addition to what others already posted... the cost is the killer