Gene therapy only works if the cargo reaches the right cells intact. Adeno-associated viruses (AAV) and lipid nanoparticles have carried the field this far, but both share a constraint: the particle is taken up into an endosome, and the payload has to escape that compartment before it is degraded. Endosomal escape is where a large share of the dose is lost, and it is why delivery, not the genetic construct, is usually the thing that limits the therapy. Lipid nanoparticles carry a second constraint, since they tend to accumulate in the liver, which narrows the diseases they can reach. What if the particle never entered that way at all?

Jitendra Kumar, Lead Scientist for Chemistry and Process Development at Entos Pharmaceuticals, works on a platform that fuses directly with the cell membrane and releases its cargo straight into the cytosol. He came to nanoparticle design the long way, through fifteen years of structural biology on the prion protein in Frankfurt and Edmonton, which is why he thinks about particle size, packaging and diffusion the way he does.

Key topics discussed:

• Jitendra’s career background in structural biology and journey to Entos Pharmaceuticals (03:18)
• The scientific motivation and challenges of working with prion proteins and breaking down complex diseases (04:55)
• Genetic medicine approaches: gain-of-function vs. loss-of-function, and the role of siRNA, ASOs, and gene delivery (06:27)
• The FAST protein platform: origins, function, and advantages for drug delivery (07:56)
• Manufacturing differences compared to LNPs, including the introduction of recombinant membrane protein production and related CMC complexity (09:55)
• Scale-up and production challenges for membrane proteins, and strategies for clinical supply (11:21)
• Clinical development progress: Phase 1/2 studies with the platform, especially for COVID vaccine delivery (12:23)
• Focus areas for the technology, including selective lung delivery and leptin therapy for lipodystrophy (13:12)
• Lessons for small biotech companies in phase 1/2 manufacturing strategy, technology transfer, and the value of an experienced network (14:31)
• Balancing process robustness with speed in new biotech ventures (16:02)
• The importance of identifying “pause steps” and must-have vs. nice-to-have features in early manufacturing processes (17:15)

Smart insight: Jitendra’s takeaway for startups: for early phases, find a partner who genuinely understands your tech and can move at your pace rather than defaulting to a big CDMO, treat your network as infrastructure, and build the ability to run production in-house. The one thing that's never up for negotiation is process robustness. The real question isn't robustness vs. speed, but how many checkpoints and safe pause points you build in so you can have both.

If this conversation got you thinking about how novel delivery vehicles reach the cell — and what it takes to carry one from bench through CMC, scale-up, and regulatory review — these four episodes go deeper:

• Episodes 125 - 126: How to Enhance Cell Engineering Using Mechanical Intracellular Delivery with Armon Sharei
• Episodes 231 - 232: From IND to BLA: The Biologics CMC Decisions That Determine Regulatory Success with Henri Kornmann
• Episodes 89 - 90: Scale-Up Secrets: Cracking the Code of AAV Production with Ahmed Youssef
• Episodes 71 - 72: Effective Outsourcing: How Small Biotech Companies Can Thrive with Mark Melville

Connect with Jitendra Kumar:

• LinkedIn: www.linkedin.com/in/jkumar2
• Email: jitendra.kumar@entospharma.com
• Website: www.entospharma.com

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