The i2c bus should be able to do this, if I've understood things correctly. You need to configure an address for each individual potentiometer (see relevant datasheets for the digipots you might be looking at), and there's an upper limit to how many you can control / bus (might have been 16?).
That'd be either midi CC messages in the digital domain, or Control Voltages in the analog.
Digital to analog converters are used to f.e. convert PWM (eg full and low voltages oscillating at a set frequency) to a continuous analog signal (such as 2.4 volts in a range of 0-3.3V). So that's how you'd get a control voltage, some microcontrollers have actual DAC chips or otherwise breakout boards are quite cheap (around 1$ / piece from China or 5x from somewhere closer). The Axo itself should have some analog out pins, you can probably search the forum.
Digipots are variable resistors, DACs give you voltage. Looking around the guitar pedal world, there's a bunch of stuff that's using LED/LDR to convert voltage to resistance, which is also available as ready-made components in the form of so called vactrols. F.e. the Chase Bliss line of pedals are completely digitally controlled using vactrols.
There's a brief comparison of approaches in this thread http://www.madbeanpedals.com/forum/index.php?topic=26504.msg256920#msg256920 , and f.e. https://www.maximintegrated.com/en/app-notes/index.mvp/id/1828 discusses issues with gain scaling.
Take the above with the appropriate grain of salt, I've yet to actually implement some of my master plans, which in the guitar pedal domain mainly involves presets or adding oscillators to control pots As for novelty, there's little new under the sun, but a lot of less-trodden paths.