Nature Biotechnology[JOURNAL]

Baysoy A, Tian X, Renauer P … +32 more , Zhang F, Bai Z, Shi H, Yang M, Zhang D, Liu M, Li H, Tao B, Enninful A, Lu Y, Gao F, Wang G, Zhang W, Tran T, Patterson NH, Sheng J, Bao S, Dong C, Xin S, Chen B, Zhong M, Rankin S, Guy C, Wang Y, Connelly JP, Pruett-Miller SM, Wang D, Xu M, Gerstein MB, Chi H, Chen S, Fan R

Nat Biotechnol · 2026 Jun · PMID 42277225 · Publisher ↗

Spatially resolved CRISPR screening in vivo has been limited to small perturbation panels and subsets of protein-coding RNAs. We present Perturb-DBiT, a method for co-sequencing of spatial total RNA whole transcriptomes... Spatially resolved CRISPR screening in vivo has been limited to small perturbation panels and subsets of protein-coding RNAs. We present Perturb-DBiT, a method for co-sequencing of spatial total RNA whole transcriptomes and single guide RNAs (sgRNAs) on the same tissue section in situ. In a human cancer metastatic colonization model, we applied large (80,000+) sgRNA panels across tumor colonies in multiple consecutive tissue sections alongside their corresponding total RNA transcriptomes. We linked perturbations affecting long noncoding RNA covariation, microRNA-mRNA interactions and distinct amino acid-specific tRNA alterations to tumor migration and growth. By integrating transcriptional pseudotime trajectories, we further observed the impact of perturbations on clonal dynamics and cooperation. In an immune-competent syngeneic mouse model, investigation of the tumor immune microenvironment indicated distinct, synergistic effects on immune infiltration and suppression. Perturb-DBiT provides a spatially resolved comprehensive view of perturbation responses in complex tissues, including small and large RNA regulation, tumor proliferation, migration, metastasis and immune interactions.

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Spatial CRISPR screens map total RNA in tissue.

Schwartz L, Pholraksa P, Goyal Y

Nat Biotechnol · 2026 Jun · PMID 42277224 · Publisher ↗

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Biotech's coming of age.

Senior M

Nat Biotechnol · 2026 Jun · PMID 42270835 · Publisher ↗

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Hybrid solid-liquid optics enable scalable, high-resolution light-sheet microscopy across diverse immersion media.

Gong C, Affatato P, Fay M … +16 more , Guttikonda SR, O'Connor NJ, Noble E, Heal M, Haydock B, Mapa R, De La Cruz ED, Gattoni G, Kowalko JE, Tosches MA, Gerfen CR, Hen R, Makinson CD, Hibshoosh H, Glaser JR, Tomer R

Nat Biotechnol · 2026 Jun · PMID 42265271 · Publisher ↗

Many data-driven approaches rely on scalable and affordable three-dimensional (3D) imaging across subcellular to organ scales. Although advances in tissue clearing, expansion microscopy and light-sheet microscopy (LSM) h... Many data-driven approaches rely on scalable and affordable three-dimensional (3D) imaging across subcellular to organ scales. Although advances in tissue clearing, expansion microscopy and light-sheet microscopy (LSM) have enabled high-resolution imaging of intact specimens, scalability in sample size, throughput and accessibility remains fundamentally limited by detection optics. Here we introduce hybrid solid-liquid optics (HySIL), a flexible refractive design framework in which a solid optical element and a refractive index (RI)-matched liquid function as a continuous optical system for wavefront correction and numerical aperture enhancement. We implement this framework as SCOPE and Super-SCOPE, enabling submicron-resolution, aberration-corrected LSM using long-working-distance air objectives. We demonstrate high-resolution volumetric imaging across diverse biological contexts, including cleared and expanded mouse, salamander and cavefish brains, human induced pluripotent stem cell (iPSC)-derived brain organoids and large intact human tissues for 3D histopathology. By combining enhanced optical performance with low-cost, long-working-distance and multi-immersion compatibility, HySIL provides an accessible and scalable foundation for next-generation volumetric imaging and data-driven biological discovery.

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Single-cell spatial pharmacobiology for imaging antibody-based therapies in solid tumors.

Nat Biotechnol · 2026 Jun · PMID 42259966 · Publisher ↗

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Next-gen cryo promises transplant surgeons more time.

Marshall A

Nat Biotechnol · 2026 Jun · PMID 42259965 · Publisher ↗

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Multiplexed, precise genome engineering in monocots with twin prime editing systems.

Li H, Chai Z, Shi X … +7 more , Sun C, Zhang R, Zhang Q, Li Z, Zhang K, Lei Y, Gao C

Nat Biotechnol · 2026 Jun · PMID 42249131 · Publisher ↗

Simultaneously introducing diverse genomic edits remains a challenge in crop genome engineering. Here we describe a twin prime editing-based knockout (TKO) system that installs stop codon clusters (SCCs) for precise tran... Simultaneously introducing diverse genomic edits remains a challenge in crop genome engineering. Here we describe a twin prime editing-based knockout (TKO) system that installs stop codon clusters (SCCs) for precise translational termination with minimal in-frame mutations. TKO achieves knockout efficiencies of up to 70.5%, 58.6% and 75.1% in rice, maize and wheat protoplasts, respectively, and produces heritable knockout alleles in 96.8% of regenerated rice plants. In hexaploid wheat, TKO outperforms Cas9 4.2-fold in generating triple-homolog knockouts, largely by reducing in-frame mutations. Orthogonal TKO editors with sequence-divergent SCCs enable simultaneous knockout of up to ten genes without cross-interference. Integration of TKO with conventional prime editing establishes TRIM1 (TKO editor-enabled gene rupture and development of integrated multitype genome modification system) for simultaneous knockout and precise editing, achieving a 22.8% coediting of four genes in rice. TRIM2 extends this capacity to kilobase-scale modifications through a prime editor-recombinase system, enabling a 4.9-kb insertion (1.2% efficiency) and gene knockout (up to 79.8%) in protoplasts.

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Structural motif search across the protein universe with Folddisco.

Kim H, Kim RS, Mirdita M … +2 more , Yoon J, Steinegger M

Nat Biotechnol · 2026 Jun · PMID 42249130 · Publisher ↗

Detecting similar protein structural motifs in large structure collections is computationally expensive. We developed Folddisco, a fast structural motif search tool that uses an index of position-independent geometric fe... Detecting similar protein structural motifs in large structure collections is computationally expensive. We developed Folddisco, a fast structural motif search tool that uses an index of position-independent geometric features, including side-chain orientation, combined with a rarity-based scoring system. Folddisco is 20-fold faster in querying and fourfold more storage-efficient than existing methods while improving accuracy. Folddisco is freely available online ( https://folddisco.foldseek.com ), along with a webserver ( https://search.foldseek.com/folddisco ).

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Marked for destruction.

Nat Biotechnol · 2026 Jun · PMID 42243498 · Publisher ↗

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Nature Biotechnology[JOURNAL]

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