In recent years, the development of nanoparticles has expanded into a broad range of clinical applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biological barriers - systemic, microenvironmental and cellular - that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one-size-fits-all solution. As lipid-based, polymeric and inorganic nanoparticles are engineered in increasingly specified ways, they can begin to be optimized for drug delivery in a more personalized manner, entering the era of precision medicine. In this Review, we discuss advanced nanoparticle designs utilized in both non-personalized and precision applications that could be applied to improve precision therapies. We focus on advances in nanoparticle design that overcome heterogeneous barriers to delivery, arguing that intelligent nanoparticle design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.

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Engineering precision nanoparticles for drug delivery

Enantiomer-dependent immunological response to chiral nanoparticles

Cancer immunotherapy has made tremendous clinical progress in advanced-stage malignancies. However, patients with various tumors exhibit a low response rate to immunotherapy because of a powerful immunosuppressive tumor microenvironment (TME) and insufficient immunogenicity of tumors. Photodynamic therapy (PDT) can not only directly kill tumor cells, but also elicit immunogenic cell death (ICD), providing antitumor immunity. Unfortunately, limitations from the inherent nature and complex TME significantly reduce the efficiency of PDT. Recently, smart nanomedicine-based strategies could subtly modulate the pharmacokinetics of therapeutic compounds and the TME to optimize both PDT and immunotherapy, resulting in an improved antitumor effect. Here, the emerging nanomedicines for PDT-driven cancer immunotherapy are reviewed, including hypoxia-reversed nanomedicines, nanosized metal-organic frameworks, and subcellular targeted nanoparticles (NPs). Moreover, we highlight the synergistic nanotherapeutics used to amplify immune responses combined with immunotherapy against tumors. Lastly, the challenges and future expectations in the field of PDT-driven cancer immunotherapy are discussed.

Recent advances in nanomedicines for photodynamic therapy (PDT)-driven cancer immunotherapy

Cancer immunotherapy is an emerging treatment strategy that modulates the immune system to fight against cancer. Although several immunotherapeutic agents have been utilized in the clinic for cancer treatment, low patient response rates and potential immune-related adverse events remain two major challenges. With the merits of delivery controllability and modular flexibility, nanomedicines provide opportunities to facilitate immunotherapies for clinical translation in a safe and effective manner. In this review, we discuss the convergence of nanomedicine with immunotherapy with a focus on molecular and nanoengineering approaches towards activatable cancer immunotherapy. These activatable nanoagents exert immunotherapeutic action only in response to internal or external stimuli. This allows them to locally reprogram the tumor microenvironment and activate antitumor immunity while reducing the incidence of immune-related adverse events. The category of activatable immunotherapeutic nanoagents are discussed along with an overview of their clinical translation prospects and challenges.

Molecular and nanoengineering approaches towards activatable cancer immunotherapy

Immunotherapy shows promising therapeutic potential for long-term tumor regression. However, current cancer immunotherapy displays a low response rate due to insufficient immunogenicity of the tumor cells. To address these challenges, herein, intracellular-acidity-activatable dynamic nanoparticles for eliciting immunogenicity by inducing ferroptosis of the tumor cells are engineered. The nanoparticles are engineered by integrating an ionizable block copolymer and acid-liable phenylboronate ester (PBE) dynamic covalent bonds for tumor-specific delivery of the ferroptosis inducer, a glutathione peroxidase 4 inhibitor RSL-3. The nanoparticles can stably encapsulate RSL-3 inside the hydrophobic core via π-π stacking interaction with the PBE groups at neutral pH (pH = 7.4), while releasing the payload in the endocytic vesicles (pH = 5.8-6.2) by acidity-triggered cleavage of the PBE dynamic covalent bonds. Furthermore, the nanoparticles can perform acid-activatable photodynamic therapy by protonation of the ionizable core, and significantly recruit tumor-infiltrating T lymphocytes for interferon gamma secretion, and thus sensitize the tumor cells to RSL-3-inducible ferroptosis. The combination of nanoparticle-induced ferroptosis and blockade of programmed death ligand 1 efficiently inhibits growth of B16-F10 melanoma tumor and lung metastasis of 4T1 breast tumors, suggesting the promising potential of ferroptosis induction for promoting cancer immunotherapy.

Acidity-Activatable Dynamic Nanoparticles Boosting Ferroptotic Cell Death for Immunotherapy of Cancer.

Immunological tolerance of tumors is characterized by insufficient infiltration of cytotoxic T lymphocytes (CTLs) and immunosuppressive microenvironment of tumor. Tumor resistance to immune checkpoint inhibitors due to immunological tolerance is an ongoing challenge for current immune checkpoint blockade (ICB) therapy. Here, we report the development of tumor microenvironment-activatable anti-PDL1 antibody (αPDL1) nanoparticles for combination immunotherapy designed to overcome immunological tolerance of tumors. Combination of αPDL1 nanoparticle treatment with near-infrared (NIR) laser irradiation-triggered activation of photosensitizer indocyanine green induces the generation of reactive oxygen species, which promotes the intratumoral infiltration of CTLs and sensitizes the tumors to PDL1 blockade therapy. We showed that the combination of antibody nanoparticles and NIR laser irradiation effectively suppressed tumor growth and metastasis to the lung and lymph nodes in mouse models. The nanoplatform that uses the antibody nanoparticle alone both for immune stimulation and PDL1 inhibition could be readily adapted to other immune checkpoint inhibitors for improved ICB therapy.

Engineering nanoparticles to locally activate T cells in the tumor microenvironment

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Engineering nanoparticles to locally activate T cells in the tumor microenvironment