Key Takeaways & Executive Findings
- •• • Manganese protoporphyrin liposomes achieved noninvasive immunogenic sonodynamic therapy against triple-negative breast cancer, inducing ICD without invasive procedures; this offers a clinical pathway for treating aggressive breast cancer subtypes with reduced systemic toxicity. • • Acoustic-triggered nanobombs enabled ultrasound imaging-guided sonodynamic therapy and activated antitumor immunity, providing real-time imaging feedback and spatiotemporal control; this dual functionality addresses the need for precise, image-guided immunotherapy. • • Mitochondrial-targeting liposomal nanosystems reinforced ICD via ultrasound-activated redox dyshomeostasis, achieving 9470–9491 Theranostics 2021 metrics; this demonstrates subcellular targeting to amplify immune activation, potentially overcoming resistance to conventional ICD inducers. • • Catalase-based liposomes reversed immunosuppressive tumor microenvironment and enhanced chemo-photodynamic therapy, with Biomaterials 2020; this combination strategy tackles hypoxia-driven immunosuppression, a major barrier in solid tumors, improving therapeutic efficacy.
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Abstract
Cancer immunotherapy is constrained by low tumor targeting, poor penetration, and immune-related adverse events. Engineered liposomal nanoplatforms mitigate these limitations by encapsulating immunotherapeutic agents within lipid bilayers, surface-modifying with targeting ligands and biocompatible polymers to reduce burst release, systemic dispersion, and rapid blood clearance. This review examines recent progress in liposome-assisted immunotherapy across cancer types, covering nanoplatform design, immunotherapy modalities, and strategies for activating immune responses. Key approaches include optimizing liposomal formulations, pairing synergistic drug combinations, and integrating with therapeutic modalities such as sonodynamic therapy, photodynamic/photothermal therapy, and checkpoint blockade. Empirical studies cited demonstrate that liposomal systems can amplify immunogenic cell death (ICD), reverse immunosuppressive tumor microenvironments, and enhance antitumor immunity. For example, manganese protoporphyrin liposomes noninvasively induce immunogenic sonodynamic therapy against triple-negative breast cancer; acoustic-triggered nanobombs enable ultrasound imaging-guided sonodynamic therapy and antitumor immunity activation; and mitochondrial-targeting liposomal nanosystems reinforce ICD through ultrasound-activated redox dyshomeostasis. Additional works show that catalase-based liposomes reverse immunosuppression and improve chemo-photodynamic therapy, while focused acoustic vortex-mediated sonochemotherapy amplifies ICD combined with checkpoint blockade. These findings underscore the potential of engineered liposomes to improve targeting, reduce toxicity, and potentiate combination immunotherapies. Remaining challenges include scalable manufacturing, long-term stability, and regulatory hurdles. Future directions involve rational design of stimuli-responsive liposomes, personalized combination regimens, and clinical translation.
1. Introduction
Cancer immunotherapy has revolutionized oncology, yet clinical translation of immunotherapeutic agents remains hampered by poor tumor accumulation, inadequate tissue penetration, and severe immune-related adverse events. Systemic administration of cytokines, checkpoint inhibitors, and antigens often results in subtherapeutic intratumoral concentrations and off-target toxicity, limiting durable responses. Conventional nanocarriers such as polymeric nanoparticles and inorganic systems face challenges including rapid clearance, burst release, and immunogenicity, underscoring the need for biocompatible, customizable delivery platforms.
Engineered liposomal nanoplatforms address these bottlenecks through lipid bilayer encapsulation, surface functionalization with targeting moieties, and stimuli-responsive design. By confining immunotherapeutic payloads within liposomal cavities and modifying surfaces with polyethylene glycol and ligands, these systems reduce burst release, evade immune clearance, and enhance tumor-specific accumulation. This review synthesizes recent experimental advances in liposome-assisted immunotherapy, detailing design principles, combination strategies with sonodynamic/photodynamic therapy, and preclinical outcomes that demonstrate amplified immunogenic cell death and reversal of immunosuppressive microenvironments. The following sections critically evaluate empirical metrics and translational hurdles.
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LIU Yang, WU Zhao-Ya, WANG Zi-Xi, KHAN Muhammad Kamran, WU Fu-Gen (2025). Engineered Liposomal Nanoplatforms for Precise Cancer Immunotherapy: Advancing Biomedical Innovations. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3621-y
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Frequently Asked Questions
What are the primary failure mechanisms of liposomal nanoplatforms under physiological stress, and how do recent designs mitigate them?
Liposomal systems face premature drug leakage, opsonization, and rapid clearance. Recent designs incorporate PEGylation to reduce protein adsorption, targeting ligands for active tumor accumulation, and stimuli-responsive lipid compositions to prevent burst release. For instance, catalase-based liposomes reversed immunosuppression and enhanced chemo-photodynamic therapy, demonstrating stability in tumor microenvironments (Biomaterials, 2020).
How do liposomal immunotherapies compare in cost and scalability against established nanoparticle platforms like polymeric or gold nanoparticles?
Liposomal manufacturing leverages established lipid film hydration and extrusion processes, enabling scalable production with lower batch-to-batch variability than gold nanoparticles. However, cost parity depends on lipid purity and functionalization steps. Clinical translation requires Good Manufacturing Practice compliance; current preclinical studies show reproducible synthesis, but large-scale sterile filtration and lyophilization remain bottlenecks.
What operational thresholds (e.g., drug-to-lipid ratio, particle size) are critical for maximizing immunogenic cell death and tumor penetration?
Optimal liposomal formulations typically maintain particle sizes of 80–120 nm for enhanced permeability and retention, with drug-to-lipid ratios of 1:10 to 1:20 to balance payload and stability. Studies on mitochondrial-targeting liposomes achieved ICD amplification with ultrasound activation, indicating that subcellular targeting and redox dyshomeostasis are key thresholds (Theranostics, 2021).
What are the long-term stability and storage challenges for engineered liposomes, and how do they impact clinical logistics?
Liposomes are prone to aggregation, lipid oxidation, and payload leakage during storage. Lyophilization with cryoprotectants (e.g., sucrose, trehalose) extends shelf-life to 12–24 months. Clinical logistics require cold-chain maintenance; however, recent formulations using biocompatible materials show improved stability, as evidenced by sustained efficacy in preclinical models (Biomaterials, 2021).
How can liposomal combination strategies overcome checkpoint blockade resistance in solid tumors?
Liposomal delivery of immunomodulators alongside checkpoint inhibitors can reprogram the tumor microenvironment. For example, focused acoustic vortex-mediated sonochemotherapy amplified ICD and combined with checkpoint blockade to potentiate immunotherapy (Biomaterials, 2023). This approach increases T-cell infiltration and reduces immunosuppressive cells, addressing resistance mechanisms.
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