Ultrasound-propelled oncolytic biomimetic microbubbles as in situ vaccines reprogram tumor immunosuppressive microenvironment

Oncolytic peptides offer a novel anticancer paradigm by inducing membrane lysis-mediated cancer cell death and subsequent anticancer immunity to overcome tumor heterogeneity and treatment resistance. Despite its promising profiles, the clinical application of oncolytic peptides (such as LTX-315) is hampered by ticklish reasons like rapid plasma clearance, suboptimal biodistribution, and potential toxicity toward normal tissues. Herein, we innovatively engineered an ultrasound-propelled cancer cell membranes-hybridized lipid microbubbles to load oncolytic peptide LTX-315 (LCMBs) for precise and controlled oncolytic therapy. The LCMBs enabled the targeted delivery and stimuli-responsive release of LTX-315 in the tumor site under low-intensity focused ultrasound (US). The high accumulation of LTX-315 and sonoporation-mediated membrane permeabilization collectively lowered the therapeutic threshold of LTX-315, improving oncolytic efficacy and reducing the off-target toxicity. LTX-315 further potentiated rapid membrane lysis and subsequent immunogenic cell death, promoting the release of tumor antigens, forming an in situ vaccine, and boosting the activation of T cells. After being combined with anti-programmed death-1 (αPD-1) therapy, the integrated LCMBs + αPD-1 regimen elicited robust anticancer immune responses, so the primary tumor, tumor recurrence, and distant metastasis were notably restrained. In summary, this study developed a novel biomimetic LCMBs delivery platform to enhance the therapeutic efficacy of highly cytotoxic oncolytic peptides and promote anticancer immunotherapy, thereby effectively inhibiting tumor recurrence and metastasis.