Hi Mittens - apart from the Bernina route through Tirano, two other obvious routes are:
1.- Interlaken Ost to Spiez to the Rhone Valley at Brig( more on that in a moment) then through the Simplon Pass from Brig to Domodossola, and on to your destination.
If it is Locarno, the train from Domodossola through the Val di Centovalli to Locarno is a special treat.
We have not worked all the major destinations in the lake region of the Ticino, but after Lugano, we tended to revisit Locarno. No strong reasons, although it felt more accessible, somehow, compared to Lugano. We enjoyed a trip into the Val Vercasca from Locarno. Also, if you are an architecture buff, you might find this worth the journey:
en.wikipedia.org/wiki/ Church_of_San_Giovanni _Battista,_Mogno
You can get to the Rhone Valley from Spiez to Visp, through the new , fast, boring Lötschberg Basis Tunnel. Form Visp, it is a short ride to Brig. Or, you can go up the valley to Kandersteg from Spiez, (on the train called the Lötschberger), go through the old tunnel to Goppenstein, then ride down the south-facing slope of the valley to Brig. Takes about an hour longer.
2,- Interlaken Ost to Luzern via the Brunig Pass ( part of the Golden Pass Route), thence to Arth-Goldau, to pick up the southbound train to the Ticino. At Bellinzona, you can choose Lugano or Locarno.
There is also a slower, nicer, named route called the Gotthard Panoramic Express, which takes a boat from Luzern to Flüelen, where you pick up the train that goes through the Gotthard Pass to Bellinzona on the old wonderfully scenic route.
Or, if you are in hurry, you can ride through the new Gotthard Basis Tunnel at high speed while studying the walls inside the tunnel.