Natalie Artzi

In vivo immune modulation can potentially benefit broader cancer patients. Efficient cross‐priming of anti‐tumor T cells requires “three‐signal” dendritic cells (DCs) that simultaneously integrate antigenic, co‐stimulatory, and migratory programs, which remains a major challenge. Here, we developed a carrier‐free peptide–cyclic dinucleotide (CDN) nanoconjugate (PCN) that co‐activates immunogenic cell death (ICD) in tumors and stimulator of interferon genes (STING) signaling in DCs. Library screening identified ICD‐inducing peptides enriched in hydrophobic and cationic residues that promote self‐assembly, cell penetration, and ICD potency. Mechanistic studies revealed peptides can trigger overlapping pyroptosis, necroptosis, and apoptosis, with lysosomal damage and cathepsin release as dominant upstream drivers. PCN promoted tumor‐antigen release and facilitated cytosolic CDN delivery for robust STING activation. This dual functionality induced early cytokine and chemokine responses and generated cDC1‐enriched “three‐signal” migratory DCs trafficking from tumors to draining lymph nodes, resulting in enhanced antigen‐specific CD8 ⁺ T‐cell activation and memory formation. PCN also broadly reprogrammed the tumor microenvironment toward anti‐tumor immunity. In preclinical models, PCN induced complete tumor rejection in 70% of B16‐F10‐ or CT26‐bearing mice and provided durable protection against tumor rechallenge when combined with α ‐PD‐1.

Cancer cells comprise a significant proportion of the tumor microenvironment (TME) and often have compromised expression or repression of cyclic GMP-AMP (cGAMP) synthase (cGAS), which prevents effective stimulation of interferon genes (STING) signaling. Here, we leverage the cancer cells and hijack their cellular machinery for increased production of cGAMP, differing from conventional strategies whereby synthetic STING agonists are delivered to immune cells in the TME as a bolus dose, are rapidly cleared and can cause systemic toxicity. Increasing evidence suggests that cGAMP derived from cancer cells can act on proximal immune cells, activating STING, contributing to an antitumor immune response. We used lipid nanoparticles (LNPs) to deliver mRNA coding for cGAS which catalyzes the production of cGAMP. We observed dramatic increases in extracellular and intracellular cGAMP when cancer cells were transfected with cGAS mRNA and genomic DNA, the substrate for cGAS. We confirmed that cGAS and cGAMP are functional due to activation of immune cells, through a combination of extracellular transfer and cell–cell contact mechanisms. Treatment of syngeneic murine melanoma with cGAS LNPs reduced tumor growth significantly and further benefit was observed upon combination with immune checkpoint blockade (anti-PD-1). Moreover, we found increased activation in CD8 ⁺ T cells, NK cells, macrophages, and dendritic cells in the TME post treatment with cGAS LNPs. These findings highlight how cancer cells can be used to actively contribute to their own elimination and may be a broadly applicable strategy for delivery of other reprogramming molecules to cancer cells and wider therapeutic combinations.

Significant advances in science and engineering often emerge at the intersections of disciplines. Nanoscience and nanotechnology are inherently interdisciplinary, uniting researchers from chemistry, physics, biology, medicine, materials science, and engineering. This convergence has fostered novel ways of thinking and enabled the development of materials, tools, and technologies that have transformed both basic and applied research, as well as how we address critical societal challenges. In this Nano Focus, we pose and explore 33 questions whose answers could profoundly impact fields such as energy, electronics, the environment, optics, and medicine. These questions highlight the need for deeper foundational understanding, improved tools and techniques, and innovative applications─each with significant societal relevance. Together, they represent a global call-to-action for the scientific community.

Structural nanomedicines are engineered constructs that arrange therapeutic components into well-defined architectures to maximize efficacy. Their multivalent, multifunctional design offers key advantages over unstructured formulations, including targeted delivery, expanded therapeutic windows, and enhanced target engagement. The mRNA COVID-19 vaccines exemplify their transformative potential. However, structural precision varies, and more well-defined architectures will streamline optimization, manufacturing, and regulation. Unlike small molecule drugs, nanomedicines within a batch are not identical. Identifying the most effective, least toxic structures will advance our understanding of structure-function relationships and therapeutic mechanisms. This work highlights structural nanomedicines─small molecules, nucleic acids, and biologics─to galvanize the field and drive innovation toward even safer, more effective treatments that benefit patients.

The lack of structural definition in nanomedicines limits therapeutic efficacy and complicates regulatory approval. Here, we emphasize that defining, designing and optimizing the structures of nanomedicines are critical to developing effective therapies because their architectures — not just the identity of their components — determines potency.

Brain tumor therapy remains limited by an immunosuppressive, monotherapy-resistant tumor microenvironment and by a paucity of technologies capable of controlling therapy delivery kinetics to the tumor. Here, we describe tissue-adhesive hydrogel-drug complexes (HDCs) for the controlled release of combination therapies synchronized with immune cycle responses following intracranial administration. Injected adhesive HDCs enabled the controlled co-delivery of multiple payloads (chemotherapy, stimulator of interferon genes agonist cyclic dinucleotide nanoparticles, immune checkpoint blockade antibodies), leading to enhanced long-term survival (>80%) and protection from contralateral hemisphere rechallenge after a single dose in multiple syngeneic orthotopic glioblastoma mouse models. Mechanistic studies revealed that tumor rejection is a consequence of reprogramming the tumor microenvironment, driven by three key phases: the initial rapid expression of inflammatory cytokines, notably IFN-γ, and tumor sensitization with antigen exposure during chemoimmunotherapy release, followed by the recruitment and subsequent sustained activation of antigen-presenting and effector cells facilitated by the hydrogel’s multiweek delivery period. These findings point to tissue-adhesive HDCs, and therapeutic release synchronized with biological responses as key considerations for realizing robust immune activation without provoking toxicity in the treatment of solid tumors.

In nanomedicine, the cellular export of nanomaterials has been less explored than uptake. Traditionally viewed in a negative light, recent findings highlight the potential of nanomedicine export to enhance therapeutic effects. This Perspective examines key pathways for export and how nanomaterial design affects removal rates. We present the idea of the "paracrine transfer effect" (PTE), where nanomaterials are first internalized by a "waypoint" cell and then exported to a "destination" cell, influencing both in potentially exploitable ways. Essential characteristics for nanomedicines to leverage the PTE are discussed, along with two case studies: STING-stimulating polymeric nanoparticles and TLR9-stimulating liposomal spherical nucleic acids. We propose future research directions to better understand and utilize the PTE in developing more effective nanomedicines.