Many cancer therapy regimes still rely heavily on the systemic administration of toxic chemotherapeutic agents. Ultrasound contrast agents consisting of microbubbles (MBs) have emerged as a drug delivery vehicle to overcome the challenges associated with systemic chemotherapy. Here, we describe the development of non-immunogenic, functionalized polylactic acid (PLA) MBs for use in targeted cancer therapy. Our previous studies have shown that the balance between acoustic behavior and improved immune avoidance was scalable and successful to different degrees with two different PEGylation methods and was best achieved using incorporation of PEG–PLA at 5 wt % and for a LipidPEG at 1 wt %. Capitalizing on this, we now attach a targeting ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which selectively induces tumor cell death upon binding to cancer cell-specific surface receptors, initiating a transmembrane apoptosis signal. Additionally, the functionalized MBs were designed to coencapsulate doxorubicin (Dox) that can be released from the polymer shell in response to ultrasound focused at the tumor site, shielding healthy tissues from toxicity while increasing the potency and efficiency of treatment to the tumor tissue. Ligation of TRAIL reduced the encapsulation efficiency for Dox compared to those of their non-ligated counterparts (p < 0.0001) by approximately 34% for 100% PLA, 23% for 5 wt % PEG–PLA, and 30% for the 1 wt % LipidPEG platform. All platforms exhibited a burst effect (<7%, p < 0.0001), and sustained release lasted for over 150 h. This work has resulted in a choice of effective ultrasound-triggered, non-immunogenic, targeted drug delivery agents for potential use in cancer therapy. These platforms have many advantages over the systemic administration of chemotherapeutic drugs and represent a promising treatment to better serve the population with solid cancerous tumors as a whole.