The only way you can know if a user opened a mail to listen for resources (images) that will download to the client (if they allow downloads) otherwise you are in the dark.
Checking the mail was sent and if the address is valid can be done but only to a certain extend the server that sends the message will report if the message could be sent but that will only be the status of the sent message on that specific server. You could setup some kind of mechanism that listens for addresses that are reported by other servers as invalid but not all the servers do this ...
You could use a third-party provider to handle the acknoweldgements for you which will lift the burden from you. Like Mailchimp but they too have limited ways to do this.
Just my 2 cents