Karl Ocius

Nature Immunology, Published online: 14 April 2026; doi:10.1038/s41590-026-02484-9

Here the authors identify a tumor immunoevasion mechanism in which tumor cells release branched-chain amino acid metabolites that can bind and activate Notch on tumor-associated macrophages, reprogramming these cells to be immunosuppressive.

Nature Chemical Biology, Published online: 17 April 2026; doi:10.1038/s41589-026-02199-w

Cell-permeable nanobodies overcome a major barrier to intracellular protein targeting. Franz, Rubil and colleagues show that delivery of a CFTR-binding nanobody into airway epithelial cells from patients with cystic fibrosis homozygous for the F508del-CFTR mutation stabilizes misfolded CFTR chloride channels and synergizes with the clinically approved modulator combination elexacaftor/tezacaftor/ivacaftor to restore CFTR function to near-normal levels.

Nature Microbiology, Published online: 16 April 2026; doi:10.1038/s41564-026-02316-4

An immunity-like system functions as a lysis control hub to promote gene transfer agent particle release from host bacterial cells, suggesting that bacterial immune systems may be co-opted to promote horizontal gene transfer.

Proceedings of the National Academy of Sciences, Volume 123, Issue 16, April 2026.
SignificanceMycobacterium aviumcan switch between two primary colony morphologies—smooth transparent (SmT) and smooth opaque (SmO)—where SmT is associated with human disease while the avirulent SmO morphotype might represent an environmental form of the ...

We introduce cell-penetrating peptides (CPPs) with polyfluoroalkyl-tags that drastically enhance intracellular protein delivery by promoting membrane retention. Via the combination of live-cell imaging, biophysical analysis, and computational simulations, we reveal how fluorous CPPs interact with membranes via monomeric interactions and dynamic tag-insertion to achieve efficient, non-cytotoxic protein delivery.

ABSTRACT

Recent advances in cell-penetrating peptide (CPP)-mediated intracellular protein delivery emphasized the critical role of sustained membrane association in enhancing delivery efficiency. Here, we report cell-surface-reactive, polyfluoroalkyl-tagged polyarginine peptides with varying fluorine content as CPP-additives that significantly enhance protein delivery in living cells. At low micromolar concentrations (2.5 µM), CPP-additives containing 11–13 fluorine atoms enhanced intracellular protein delivery over 2-fold relative to a tagless control without observable cytotoxicity. Live-cell time-lapse fluorescence imaging revealed that a CPP-additive with 13 fluorine atoms showed prolonged membrane association (>5 min) relative to a tagless control and facilitated rapid protein internalization within 10 min. Remarkably, surface-enhanced infrared absorption spectroscopy (SEIRAS) with POPC membranes showed that fluorous CPP-additives initially interacted with the lipid bilayer predominantly as aggregates but subsequently inserted into the membrane interior as monomers without fluorous tag-tag association. Complementary molecular dynamics simulations of the initial membrane-association step provided atomistic insight, showing partial lipid insertion of a monomeric CPP-additive with 13 fluorine atoms while no insertion was observed for a tagless control within the same time scale. Collectively, our findings establish polyfluoroalkyl-tagged CPP-additives as potent, non-cytotoxic vectors for intracellular protein delivery and provide mechanistic detail regarding the molecular basis of their lipid bilayer interactions.

Nature Chemistry, Published online: 13 April 2026; doi:10.1038/s41557-026-02116-7

Hydrophobicity plays an important role in protein function, but tuning hydrophobicity with canonical amino acids is chemically limited. Now through the genetic incorporation of bulky, highly hydrophobic non-canonical amino acids, their utility in enzyme engineering by enhancing the function of a copper-dependent laccase through hydrophobic tuning has been demonstrated.

Gut-derived bacterial DL-endopeptidase may confer protection from late onset sepsis (LOS) in preterm infants. In this issue of Cell Host & Microbe, Shen et al. identified delayed gut microbiome development in preterm infants as a risk factor for LOS and proposed a protective regulatory response by NOD2.

Nature Communications, Published online: 06 April 2026; doi:10.1038/s41467-026-71395-y

CAR T cell therapies are effective but costly and difficult to manufacture. Here, authors develop a novel approach using retargeted and functionalized lentiviral vectors that selectively reprogram T cells in vivo, evade immune clearance, and generate functional CAR T cells with therapeutic efficacy.

Nature Communications, Published online: 08 April 2026; doi:10.1038/s41467-026-70751-2

PD-1 blockade provides clinical benefit in gastrointestinal cancers, yet the sites and immune cell populations initiating effective anti-tumor immunity through the treatment remain unclear. The authors here show that anti-PD-1 antibodies activate PD-1⁺TCF1⁺ progenitor exhausted CD8⁺ T cells in lymph nodes that expand and infiltrate tumors to mediate immunity.

So let’s finally talk about peptides. And I don’t mean peptides as chemists and biologists understand them (short chains of amino acids) I mean “Peptides!”, the hot new wonder drugs that you can order by mail. Oh man.

The first barrier to writing about this situation, for someone like me, is that difference in terms. For a chemist, “peptide” has a pretty clear definition: any relatively short chain of amino acids, and when they get longer we go ahead and call them “proteins”, although the dividing line is a matter of personal opinion. So the number of different possible peptides is just ridiculously huge. If you just pick (say) a ten-amino-acid chain with the 20 common amino acids, that’s twenty to the tenth power, which is over ten trillion possibilities. For comparison, it has been about ten trillion seconds since Homo sapiens emerged as a separate species.

And since that number is large and contains multitudes, there are lots of physiologically active peptides and an even much more gigantic mass of them that biologically do nothing at all. As you digest any particular piece of protein (being from Arkansas, I recommend a plate of barbecue or fried catfish) the enzymes in your stomach and small intestine are producing huge numbers of progressively shorter peptide chains as they break down that food on the way to stuff that will be absorbed into the bloodstream. And this is while every living cell is making progressively longer peptide chains off the ribosomes, building back up the proteins needed for life. This is why I I had a puzzled look on my face when I first saw people talking excitedly about how they were taking “peptides” as if that were a well-defined category that everyone knew about.

Mentioning digestion brings up the question of stability. Your body is also awash with enzymes (proteins themselves!) that do a terrific job of breaking down peptide bonds. So the lifetime of any random protein string in the blood is probably going to be limited, but the subject of today’s post is not random peptides. Nope, it’s amazing wonder peptides ordered from suppliers who mail them directly to your house, stuff that will variously energize your waking hours, cure your diseases, melt your fat deposits, build your muscles, grow your hair, and extend your lifespan. You’re not going to be taking these things orally, because unless a really substantial amount of engineering has gone into it, any given peptide is going get the same treatment from your digestive system as a chicken breast does, i.e. a complete teardown. These mail-order peptides are injectable items.

At one point that would have severely limited their use, but the advent of the GLP-1 drugs (proteins as well, which are largely but not exclusively injectables) has made this more acceptable, at least among people who don’t know someone who has to inject insulin (which needless to say is a small protein itself). So the times have come around to make this a real business opportunity, which many suppliers are enthusiastically leaning into.

How about the science? It’s the biggest mixed bag you ever saw. There’s no doubt at all that there are some extremely biologically active peptides out there, and more such things are being discovered all the time. In fact, there’s a whole field devoted to looking at peptides that are too short to have been studied by the usual analyses, and those folks are turning up all sorts of activities that we never even appreciated were there. So that’s the first point: there are indeed a whole range of physical and medical effects to be found in these things.

Unfortunately, point two is that we barely have any of these effects worked out - at least not to the degree that you would want before you start injecting them into your leg. We’re still finding things out about extremely well known active proteins like insulin, much less more recent discoveries. That lack of knowledge extends - and how - both to their on-target effects (assuming that the target or targets are reasonably well known, which isn’t always the case) and to their off-target toxicities. 

And there are going to be plenty of cases where yes, Peptide X sure does do that thing you’re interested in, but it turns out that you can’t do That Thing without doing other things that you are surely not interested in. A number of “peptides of abuse” these days, for example, seem to be targeting human growth hormone pathways and associated ones, so let’s use that as an example. The pitch is often something like “Here’s the signal your body uses to build muscle! Take it directly and get going today!”, and with HGH there’s also been a longstanding subculture that treats it as a Fountain of Youth signal of some kind. “Replenish your growth hormone levels”, the idea is, “and dial back the biological clock!”

But growth hormone (and I shouldn’t have to say this) is powerful stuff, and it doesn’t just go tell your muscles to swell up. It affects bone tissue and many other tissues as well. I would invite anyone looking to maximize their growth hormone levels to look up a condition called acromegaly, which is what you get when your body keeps on making more growth hormone than you strictly need. Bones in the hands, feet, and head enlarge, and you get all sorts of side effects like joint pain, high blood pressure, type II diabetes, and other things that are probably not mentioned in the peptide supplier’s brochure. 

Excess growth hormone also increases the risk of some types of cancer, and that is a general problem with any attempt to (re)activate cellular growth pathways. Cancer, when you get right down to it, is a disease of unrestrained cellular growth, and there are a lot of different pathways that can lead to it. Stimulating cell growth out of the blue with systemic injections of synthetic hormone-like peptides is (in my view, and it ain’t just me) an invitation to greater tumor risk. And that’s just for starters. 

There are two very good pieces over at Stat right now on this topic. One, by physician Vikas Patel, describes a patient who is discontinuing her statin therapy - very inadvisably, given the clinical presentation described - but is enthusiastic about “BPC-157” as an injectable peptide for her knee pain. Says Patel:

My patient is refusing a drug studied in 170,000 people because of side effects that a 124,000-person analysis just confirmed do not exist — while injecting a compound studied in 14 humans, from unregulated sources, based on the recommendation of someone who profits from selling it. She’s probably not the only one. And those using it believe they are “doing their own research.”

The other one (by Sarah Hood) relates all this to RFJ Jr.’s advocacy. The flip side of “the government shouldn’t be able to force me to vaccinate my kids” is “I should have the right to take whatever medicines I want to without the government getting in my way”. That’s what we’re seeing here. I would bet that many peptide customers see themselves as free agents who have done their own research and are taking their health into their own hands - and dodging past Big Med and the old fossils at the regulatory agencies while they’re at it. But as that article points out (and as I’m doing today), what they’re actually doing is rolling the dice after falling for sales pitches aimed at exactly this sort of customer.

That dice rolling doesn’t just end at the unknown mechanisms of action, the lack of human data, and the lack of information about potential side effects. You’re also ordered from suppliers whose manufacturing standards you are in no position whatsoever to check, no matter how much of a free health warrior you might be. You don’t have an LC/MS or an NMR machine in your garage, so you can’t be sure what it is you’re really injecting, how pure it is, or to what extent it’s already deteriorated on standing. There is no one at the other end of the deal who cares very much, either, believe me. Human nature being what it is in this fallen world, you actually need regulatory agencies to force people to care about these issues by threatening them with severe punishments if they don’t.

In my own view (and it ain’t just me) you also have regulatory agencies to force people to show that their drugs actually have some benefit before they can sell them, too. But that’s going further and further out of fashion. Can’t get ahold of the New Hotness to inject into your upper thigh if there are a bunch of stick-in-the-mud folks asking for human data, infringing on your freedom and all. What a time to be alive.

Nature Microbiology, Published online: 08 April 2026; doi:10.1038/s41564-026-02309-3

Emerging multidrug-resistant Neisseria gonorrhoeae is a global health threat in the treatment of gonorrhoea. This study reports the discovery and characterization of a promising antigonorrhoea agent that addresses antibiotic resistance.

Nature Microbiology, Published online: 07 April 2026; doi:10.1038/s41564-026-02322-6

Sequential peptidoglycan carboxylase activity of DacA and DacB generates a local peptidoglycan signature that recruits MapZ and establishes the division site at the Streptococcus pneumoniae cell equator.

Backbone macrocyclic peptide library (BMP) library was screened against Akt2 via RaPID to discover potent BMPPakti-3 (IC₅₀ = 34 nM).

ABSTRACT

Backbone-cyclic peptides (BMPs) are an attractive class of molecules appeared in diverse natural bioactive products. However, mRNA display technology coupled with ribosomal synthesis is intrinsically inapplicable to such peptide phenotypes due to loss of the C-terminal peptide region linking to the mRNA genotypes. To overcome this issue, we have devised a new strategy to link the sidechain-to-S-mainchain bond via an S-to-N acyl-shift to connect BMPs to the C-terminal fragment of the peptide. Here, we report the application of this strategy to construct a library of BMPs fused to cognate mRNAs. The library was applied for the selection of BMP ligands targeting Akt2, which is involved in the signal pathway to cancer pathogenesis. Consequently, BMP ligands against Akt2 were successfully uncovered from the library. The most potent Akt2 inhibitor, BMPakti-3, showed 1.3 nM of dissociation constant and 34 nM of half-maximal inhibitory concentration (IC₅₀). This system offers a unique platform for the de novo discovery of bioactive BMP ligands against various protein targets of interest.