The aim of this first-in-human clinical study is to explore the safety, tolerability, pharmacodynamics, and exploratory efficacy of PIEZO-101, an investigational plasmid DNA biostimulator that aims to restore expression of key proteins in the skin for extracellular matrix rejuvenation. PIEZO-101 is administered using an intradermal injection followed by localized electroporation using the investigational device Piezopen. This clinical trial will study safety and tolerability, pharmacodynamics using biopsies from the left knee, and exploratory efficacy using photography on the décolleté. Up to 8 participants may be enrolled to ensure 6 evaluable participants complete the study.

Inclusion Criteria (Participants must meet ALL of the following criteria to be eligible for enrollment):

1. Healthy female adults aged 40-65 years
2. Fitzpatrick skin phototype score I-IV
3. Visible signs of skin laxity, wrinkling, or crepiness in the knee area, confirmed by photographic documentation reviewed by at least two independent assessors
4. Visible signs of wrinkling or crepiness in the décolleté area suitable for standardized photography, free of tattoos, significant scarring, or confounding skin conditions in the photography field, confirmed by photographic documentation reviewed by at least two independent assessors
5. Willingness to undergo all protocol-required skin punch biopsies (four at Day 7 and four at Day 35) from the knee area
6. Willingness to abstain from other aesthetic or dermatologic treatments in the knee and décolleté areas during the study
7. For women of childbearing potential (WOCBP): commitment to use a highly effective method of contraception (combined hormonal contraception, progestogen-only contraception, intrauterine device or hormone-releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence) from the Screening Visit through the Day 90 End-of-Study visit. Postmenopausal status, defined as ≥12 months of natural amenorrhea, is not considered childbearing potential.
8. Negative serum β-hCG pregnancy test at the Screening Visit (Visit 1) and negative urine pregnancy test at the treatment visits (Visit 2 and Visit 6) prior to dose for participants of child-bearing potential
9. Willing and able to comply with all scheduled visits (10 study site visits), treatment plan, and study procedures for the full 90-day study duration
10. Able to understand and willing to sign a written informed consent document.

Exclusion Criteria (Participants must meet NONE of the following criteria to be eligible for enrollment):

1. History of keloid or hypertrophic scarring
2. Known allergy or hypersensitivity to any antibiotic
3. Known hypersensitivity to lidocaine, prilocaine, or any component of the topical anesthetic preparation
4. Active dermatologic conditions or infections (such as psoriasis, eczema, active acne, or dermatitis) in the knee or décolleté treatment areas
5. History of knee surgery or significant scarring in the knee treatment area; history of breast augmentation, reduction, or surgery resulting in scarring in the décolleté treatment area
6. Use of systemic corticosteroids, immunosuppressants, or medications affecting wound healing within 30 days of Day 0
7. Known autoimmune disease or immunodeficiency
8. Pregnancy or breastfeeding
9. Participation in another investigational study within 30 days of Day 0
10. Known allergy to metals such as stainless steel
11. Prior gene therapy of any kind (for clarity, prior receipt of RNA and DNA vaccines is not exclusionary)
12. Implanted electronic device (e.g., cardiac pacemaker, defibrillator, neurostimulator)
13. Any aesthetic procedure (injectable, energy-based device, laser, filler, biostimulator, chemical peel, topical prescription product) in the knee or décolleté areas within 6 months of screening
14. Tattoos, permanent makeup, or scarring in the knee or décolleté treatment areas that could interfere with clinical or photographic assessments
15. History of any malignancy within 5 years prior to screening, except adequately treated basal cell or squamous cell carcinoma of the skin outside the treatment areas
16. Any condition that, in the opinion of the PI, would compromise participant safety or study integrity.